Macrolides with antibacterial activity

ABSTRACT

The invention provides new macrolides antibiotics of formula I with improved biological properties and having the formula  
                 
 
     wherein R 1 , R 2  and R 3  are as herein described.

BACKGROUND OF THE INVENTION

[0001] This invention relates to new macrolide antibiotics with improvedactivity and methods of making them, the use of such antibiotics for thetreatment of infectious diseases and compositions containing suchmacrolides.

[0002] The interest in macrolide antibiotics is increasing because thesecompounds are a very effective and safe class of agents against grampositive pathogens. Extensive spread of erythromycin A resistance amonggram positive cocci isolates raised the urgent need for novelderivatives with improved activity, stability and antimicrobial spectra.The two most successful second generation agents derived fromerythromycin A (Compound 1) through semisynthesis were its 6-O-methylderivative clarithromycin (Compound 2) and the 15-membered azalideazithromycin (Compound 3) arising from a Beckman rearrangement. However,while featuring improved pharmacokinetics, none of these agentspossessed a significant activity against bacterial isolates showingmacrolide-lincosamide-streptogramine B (MLS B) cross resistance.

[0003] Many different semisynthetic third generation derivatives of theketolide class of macrolide antibiotics have been described, the mostpotent being HMR 3647 or telithromycin (Compound 4) (EP 680967 Al(1995); FR 2732684 Al (1996); Bioorg. Med. Chem. Lett. (1999), 9(21),3075-3080.) and ABT 773 (WO 9809978 (1998); J. Med. Chem. 2000, 43,1045). However, none of these agents described thus far have been ableto overcome constitutive MLS B resistance in Staphylococctis aureus.

SUMMARY OF THE INVENTION

[0004] The invention provides new macrolide antibiotics of formula Iwith improved biological properties, i.e. having the formula

[0005] wherein R¹, R² and R³ and as herein described.

[0006] The compounds of the present invention are new and possess potentantimicrobial properties against gram positive and selected gramnegative organisms. Therefore, they are useful as agents against grampositive pathogens such as staphylococci, streptococci and pneumococcias well as some gram negative strains such as H. influenzae and may beused in human or veterinary medicine for treatment or prevention ofinfections caused by susceptible organisms.

DETAILED DESCRIPTION OF THE INVENTION

[0007] The invention provides new macrolide antibiotics of formula Iwith improved biological properties, i.e. having the formula

[0008] wherein

[0009] R¹ is hydrogen, cyano or a residue -Y-X-Q;

[0010] Y is S, SO, SO_(2,) NH, NCH_(3,) CH₂O, CH₂NH, CH₂NCH₃ or CO;

[0011] X is a bond or a linear group with up to 9 atoms consisting of C,N, O and/or S, of which up to 2 atoms can be N, one atom can be O or S,one carbon atom can appear as a CO group, one sulphur atom can appear asan SO₂ group and two adjacent C atoms can be present as -CH=CH- or-C=-C-;)

[0012] Q is hydrogen, alkyl, heterocyclyl or aryl , which heterocyclyland aryl groups may be further substituted;

[0013] R² is hydrogen or fluorine;

[0014] R³ is methyl, -(CH₂)₃-R⁵, -CH₂CH=CH-R⁵ or -CH₂C≡C-R⁵;

[0015] R⁵ is heterocyclyl or aryl, which heterocyclyl and aryl groupsmay be further substituted;

[0016] z is O or NOR⁴;

[0017] R⁴ is hydrogen, alkyl, heterocyclyl, aryl, heterocyclylalkyl oraralkyl; indicates a chiral centre which is in the (R) or (S) form, i.e.including diastereomeric mixtures and separate stereomeric forms, andpharmaceutically acceptable acid addition salts or in vivo cleavableesters thereof, provided that not simultaneously R² is hydrogen, R³ ismethyl and Z is 0 when simultaneously

[0018] R¹ is hydrogen, cyano, -S(L)mR⁶, -S(O)(L)mR⁶, or -S(0)₂(L)mR⁶;

[0019] L represents -(CH₂)n- or -(CH₂)nZ¹(CH₂)_(n)′-;

[0020] m is 0 or 1;

[0021] n is 1, 2, 3, or 4;

[0022] n¹ is 0,1,2,3, or4;

[0023] Z¹ is O, S or NH; and

[0024] R⁶ is hydrogen, alkyl, heterocyclyl or aryl; which heterocyclyland aryl groups may be further substituted.

[0025] As used herein the term “alkyl” refers to straight or branchedchain saturated hydrocarbon group having 1 to 12 carbon atoms,preferably 1 to 6 carbon atoms. Such groups are for example methyl,ethyl, n-propyl, isopropyl, tertiary butyl, pentyl, hexyl, and the like.

[0026] The term “halogen” refers to chlorine, bromine or iodine.

[0027] The term “aryl” refers to 6-membered, aromatic groups with one ormore nuclei from 6 to 14 carbon atoms. Examples are phenyl, naphthyl,anthryl and phenanthryl. These groups may be further substituted with1,2,3,4 or 5 substituents selected from, for example, phenyl, alkyl,lower alkoxy such as methoxy, ethoxy, propyloxy or n-butoxy, halogen,hydroxy, amino, alkylamino, dialkylamino, nitro or cyano. They can beidentical or different from each other. In case more than onesubstituent is attached to the aryl group, these substituents can beidentical or different from each other and are also encompassed by thescope of the present invention. For example dimethoxy-phenyl means thatboth methoxy substituents may be attached to the phenyl ring in the2,3-position, the 2,4-position, the 2,5-position, the 2,6-position, the3,4-position, the 3,5-position and the 3,6-position.

[0028] Examples of substituted aryl rings are p-methoxy-phenyl,p-dimethylamino-phenyl, p-cyano-phenyl,5-(dimethylamino)-1-naphthalenyl, 2,4-dimethoxyphenyl,2′-methoxy-1,1′-biphenyl, 3,4-dimethylphenyl,

[0029] As used herein the term “heterocyclyl” refers to an unsaturatedor saturated, unsubstituted or substituted 5-, 6-, or 7-membered (mono-or bicyclic) heterocyclic ring system containing at least one heteroatom selected from the group consisting of oxygen, nitrogen, and/orsulfur. Exemplary heterocyclic substituents include, but are not limitedto, for example, the following groups: piperidinyl, morpholinyl, 2-, 3-or 4-pyridyl, pyrrolidinyl, piperazinyl, 1H-pyrazol-1-yl,1H-imidazol-1-yl, 1H-imidazol-2-yl, pyrazinyl, pyrimidyl, pyridazinyl,pyrazolyl, triazinyl, thiazolyl, thiadiazolyl, oxadiazolyl, triazolyl,e.g. 1H-[1,2,4]-triazol-1-yl, 1H-tetrazolyl, 2H-tetrazolyl; thienyl,furyl (2-furanyl or 3-furanyl), 1H-azepinyl, tetrahydrothiophenyl,3H-1,2,3-oxathiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadithiolyl,isoxazolyl, isothiazolyl, 4H-1,2,4-oxadiazinyl, 1,2,5-oxathiazinyl,1,2,3,5-oxathiadiazinyl, 1,3,4-thiadiazepinyl, 1,2,5,6-oxatriazepinyl,1,6,3,4-dioxadithiopanyl, oxazolidinyl, tetrahydrothienyl, and the like,or condensed heterocyclic ring systems such as quinolinyl, e.g.quinolin-8-yl, quinolin-5-yl, quinolin-2-yl, quinolin-6-yl,quinolin-3-yl, isoquinolinyl (6-isoquinolinyl), quinazolinyl,lH-benztriazolyl, 1H-imidazo [4,5-cl pyridinyl, 5H-imidazo[4,5-c]pyridinyl, lH-imidazo [4,5-b]pyridin- 1-yl, 3H-imidazo[4,5-b]pyridin-3-yl, 1 ,2,3,4-tetrahydro-quinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, thieno[2,3-b]pyridinyl, benzothiazolyl(e.g. 2-benzothiazolyl), 1H-benzoimidazolyl, 1H-indolyl,1,2,3,4-tetrahydroquinolinyl, purinyl, e.g. 9H-purin-9-yl,6-amino-9H-purin-9-yl, 1H-purin-6-yl, 1H-2,3-dihydroindol-1-yl,2,1,3-benzoxadiazol-5-yl, 2,1,3-benzoxadiazol-4-yl,1,3-benzodioxol-5-yl, 2-benzo[b]thien-3-yl,3,4-dihydro-1H-2-oxo-quinolin-6-yl.

[0030] The aryl or heterocyclyl groups may be further substituted by oneor more substituents. Such substituents include, for example, alkylgroups such as defined above, alkoxy groups such as methoxy, ethoxy,propyloxy or butyloxy, halogen such as fluorine, chlorine, bromine oriodine, halogen substituted alkyl groups such as trifluoromethyl,trichlroethyl, nitro, amino, alkylamino, dialkylamino, alkylthio,mercapto, hydroxy, carbamoyl, a carboxyl group, an oxo group; orunsubstituted or substituted aryl as defined above; or heterocyclyl.

[0031] In case more than one substituent is attached to the heterocyclylgroup, these substituents can be identical or different from each otherand are also encompassed by the scope of the present invention. Forexample dimethylpyridyl means that both methyl substituents may beattached to the pyridyl in the chemically possible positions. Forexample both methyl substituents may be attached to the 2-pyridyl in the3,4-position, the 4,5-position, the 5,6-position, the 3,5-position, the3,6-position, the and the 4,6-position. Both methyl substituents may beattached to the 3-pyridyl in the 2,4-position, the 2,5-position, the2,6-position, the 4,5-position, the 4,6-position, the and the5,6-position. Both methyl substituents may be attached to the 4-pyridylin the 2,3-position, the 2,5-position, the 2,6-position, and the3,5-position.

[0032] Examples of substituted heterocyclyl groups are5-(2-pyridinyl)thien-2-yl, 5-methyl-3-isoxazolyl, 5-cyanopyridin-2-yl;6-(lH-imidazol-1-yl)-3-pyridinyl, 6-(1H-pyrazol-1-yl)-3-pyridinyl,6-bromo-2-methyl-quinazolin-4-yl.

[0033] Especially preferred substituents for the heterocyclyl groups arealkyl, alkoxy, oxo, amino, alkylamino, dialkylamino or unsubstituted orsubstituted aryl. Examples of preferred substituted heterocyclic ringsare 1H-pyrimidin-2,4-dione-1-yl,1H,3H-pyrimidin-2,4-dione-5-methyl-1-yl, 1H-pyrimidin-4-amino-2-one-1-yl, 6-amino-9H-purin-9-yl, 6-dimethylamino-9H-purine-9-yl,4-phenyl-1H-pyrazol-1-yl, 3-(pyridin-3-yl)-1H-pyrazol- 1-yl,3-(pyridin-4-yl)- lH-pyrazol- l-yl, 3-(pyridin-3-yl)-1H-imidazol-1-yl,3-(pyridin-4-yl)- lH-imidazol- 1-yl, 3-(pyridin-3-yl)- 1H-[1,2,4]triazol-1-yl, 3-(pyridin-4-yl)-1H-[,2,4]triazol-1-yl and2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl.

[0034] In the combinations “heterocyclylalkyl” and “aralkyl” thecomponents “hetero-cyclyl”, “ar” (aryl) and “alkyl” have the meaningsindicated above.

[0035] Preferred groups Q are:

[0036] Another preferred group Q is

[0037] Further preferred groups Q are:

[0038] The symbol X represent a bond; i.e. is “absent” or a spacer whichis a linear group with up to 9 atoms and defined as above. The lineargroup with up to 9 atoms may carry additional hydrogen atoms, tosaturate a C atom being a methylen group or to saturate a N atom beingan amino group. Preferably, this spacer consists of 2 to 5 atoms.

[0039] Preferred groups X are:

[0040] (CH₂)n, (CH₂)mOCH₂, (CH₂)₂NCH₃(CH₂)₂, and (CH₂)_(p)COW, where nand p are 1-3, m is 0-3 and W is absent or O or NH.

[0041] Further preferred groups X are: (CH₂)_(n), (CH₂)_(m)OCH₂,(CH₂)₂NCH₃(CH₂)₂, CH₂CH₂NH and (CH₂)_(p)COW, where n and p are 1-3, m is0-3 and W is absent or O or NH.

[0042] Preferred groups Y are: S, SO₂ and CO; particularly S.

[0043] Further interesting groups Y are: CH₂O, NH and CH₂NH.

[0044] Combinations of Y and X are:

[0045] For Y=S, X is ethyl, propyl, CH₂CO, CH₂COCH₂, CH₂CONR,CH₂CONRCH₂, CH₂CONRCH₂CH₂, CH₂CH₂CONR, CH₂CH₂CONRCH₂, CH₂CH₂NRCO,CH₂CH₂NRSO₂, CH₂CH₂NRCOO, CH₂CH₂OCH₂, CH₂SO₂NR, CH₂SO₂NRCH₂,CH₂CH₂OCONR, CH₂CH=CH or CH₂C=C;

[0046] For Y=CO, X is NRCH₂, NRCH₂CH₂ or NRCH₂CH₂CH₂;

[0047] For Y=CH₂O, X is CONR, CONRCH₂, CH₂CH=CH or CH₂C=-C;

[0048] For Y=NH, CH₂NH or CH₂NHCH₃, X is COCH₂, COCH₂CH₂, COCH₂CH₂CH₂,COO or COOCH₂;

[0049] R in the above expressions being hydrogen or methyl.

[0050] Preferred group R¹ are

[0051] Further preferred groups R¹ are

[0052] Further interesting group R¹ are:

[0053] Preferred groups R³ are methyl,

[0054] Preferred compounds of formula I are the following: Example R¹ R²R³ Z  1

F Me O  2

F Me O  3

H Me O  4

H Me O  5

H Me O  6

H Me O  7

H Me O  8

H Me O  9

H Me O 10

F Me O 11

F Me O 12

F Me O 13

F Me O 14

F Me O 15

H

O 16

H Me O 17

H Me O 18

H Me O 19

H Me O 20

H Me O 21

H Me O 22

H Me O 23

H Me O 24

H Me O 25

F Me O 26

H Me O 27

H Me O 28

H Me O 29

H Me O 30

H Me O 31

H Me O 32

H Me O 33

H Me O 34

H Me O 35

H Me O 36

H Me O 37

H Me O 38

H Me O 39

H Me O 40

H Me O 41

H Me O 42

H Me O 43

H Me O 44

H Me O 45

H Me O 46

H Me O 47

H Me O 48

H Me O 49

H Me O 50

H Me O 51

H Me O 52

H Me O 53

H Me O 54

H Me O 55

H Me O 56

F Me O 57

F Me O 58

F Me O 59

H Me O 60

H Me O

[0055] Partcularly preferred are the compounds of Examples 12, 13 and56.

[0056] If desired, compounds of formula I can be converted into apharmaceutically acceptable acid addition salt. The salt formation iseffected at room temperature with methods which are known per se andwhich are familiar to any person skilled in the art. Not only salts withinorganic acids, but also salts with organic acids come intoconsideration. Hydrochlorides, hydrobromides, sulfates, nitrates,citrates, acetates, trifluoroacetates, maleates, succinates,methanesulphonates, p-toluenesulphonates and the like are examples ofsuch salts.

[0057] Further, the compounds can be converted into in vivo cleavableesters, for example into esters with the 2′-hydroxy group of the sugarmoiety, such esters are e.g. acetates, pivaloyl, esters, tartrates,maleates, succinates, and the like. These esters can be preparedaccording to methods known in the art, for example by reaction with anappropriate anhydride.

[0058] The compounds of the present invention and their pharmaceuticallyacceptable acid addition salts or in vivo cleavable esters thereof areuseful as antibacterial therapeutics. Compounds of formula I possessexcellent antibacterial activity against selected pathogenic bacteriasuch as strains of Staphylococcus auretis and Streptococcus pneumoniae.They can thus be used as medicaments for the treatment of infectiousdiseases, especially of infections caused by staphylococci such assepticemia, skin and soft tissue infections, deep infections aftertrauma, surgery, or insertion of foreign material, endocarditis,pneumonia, arthritis, bursitis, and osteomyelitis; or infections causedby streptococci such as septicemia, skin and soft tissue infections,deep infections after trauma, surgery, or insertion of foreign material,endocarditis, tonsillopharyngitis, pneumonia, bronchopneumonia,bronchitis, otitis, sinusitis, and scarlet fever.

[0059] Furthermore, the compounds of formula I can be used asmedicaments for the treatment of infections caused by germs such asMoraxella catarrhalis, Haemophiltis spp., Neisseria spp., Legionellaspp., Mycoplasma spp., Ureaplasma tirealyticum, Rickettsia spp.,Bartonella spp., Coxiella butrnetti, Chlamydia spp., or susceptiblestrains of Mycobacteritim spp., Nocardia spp., and Actinomyces spp.

[0060] The antibacterial activities of the compounds have beendetermined by standard microdilution technique (National Committee forClinical Laboratory Standards. 2000. Methods for Dilution AntimicrobialSusceptibility Tests for Bacteria that Grow Aerobically, 5^(th) edition.Approved standard M7-A5. National Committee for Clinical LaboratoryStandards, Wayne, Pa.). The activities expressed as the minimuminhibitory concentrations (MICs) (μg/ml) are given in the followingTable.

[0061] The biological activities of compounds of the present inventionagainst Haemophiltis influenzae have been determined by standard agardilution method using HTM medium (National Committee for ClinicalLaboratory Standards. 2000. Methods for Dilution AntimicrobialSusceptibility Tests for Bacteria that Grow Aerobically, 5^(th) edition.Approved standard M7-A5. National Committee for Clinical LaboratoryStandards, Wayne, Pa.). Their MICs along with MICs of selected referencecompounds are given in the following Table. Microorganism CodeStaphylococcus aureus ATCC 29213 A Staphylococcus aureus 1086 BStaphylococcus aureus 745 C Escherichia coli ATCC 25922 D Streptococcuspneumoniae l/l E Streptococcus pneumoniae ¼ F Streptococcus pneumoniaeSL199T G Streptococcus pneumoniae 12288 H Haemophilus influenzae QK12/87I Haemophilus influenzae 12214 K Haemophilus influenzae QK50 LHaemophilus influenzae B1501 M

[0062] Strain Example A B C D E F G H I K L M 1 2 2 >32 >32 0.5 832 >32 >32 >32 32 32 2 2 2 >32 >32 <=0.06 4 >32 >32 >32 >32 32 >32 3 22 >32 >32 <=0.06 16 32 >32 >32 >32 >32 >32 4 <=0.06 <=0.06 >32 >32<=0.06 <=0.06 1 4 2 2 2 1 5 1 1 >32 >32 0.125 >32 >32 >32 32 32 32 16 61 1 >32 >32 <=0.06 >32 32 >32 >32 32 32 32 7 1 0.5 >32 >32 <=0.06 3232 >32 32 32 32 32 9 1 1 >32 >32 <=0.06 0.5 8 32 8 16 8 4 10 0.50.5 >32 >32 0.5 2 8 16 32 >32 32 >32 11 0.125 <=0.06 >32 >32 <=0.06 0.254 16 8 8 4 4 12 <=0.06 <=0.06 >32 >32 <=0.06 <=0.06 0.25 4 8 4 4 4 13<=0.06 <=0.06 >32 32 <=0.06 <=0.06 <=0.06 0.25 2 2 2 2 14 <=0.06<=0.06 >32 >32 <=0.06 2 1 16 2 2 2 2 15 <=0.06 <=0.06 32 >32 <=0.06 0.252 16 4 4 2 2 16 nd nd nd Nd nd nd nd nd nd nd nd nd 17 16 8 >32 >321 >32 >32 >32 >32 >32 >32 >32 18 0.25 0.25 >32 >32 <=0.06 2 16 >32 8 8 88 19 0.25 0.25 >32 >32 0.125 2 32 >32 4 4 8 4 20 <=0.06 <=0.06 >32 >32<=0.06 0.5 8 >32 2 2 4 2 21 0.125 0.125 >32 >32 <=0.06 8 16 32 32 16 1616 22 <=0.06 <=0.06 >32 >32 <=0.06 8 8 >32 4 4 4 4 23 16 16 >32 >321 >32 >32 >32 >32 >32 >32 >32 24 2 1 >32 >32 <=0.06 >32 32 >3232 >32 >32 32 25 0.25 0.125 32 >32 <=0.06 0.125 2 4 8 4 4 8 26 0.250.25 >32 >32 <=0.06 0.125 1 4 4 2 2 4 27 <=0.06 <=0.06 >32 >32 <=0.06 88 >32 16 16 16 8 28 1 1 >32 >32 <=0.06 32 16 >32 32 >32 32 >32 29 <=0.06<=0.06 >32 >32 <=0.06 >32 2 >32 8 8 8 8 30 0.125 <=0.06 >32 >32 <=0.0632 16 >32 16 16 16 8 31 0.5 0.25 >32 >32 <=0.06 >32 32 >32 8 8 8 8 32 10.5 >32 >32 <=0.06 >32 32 >32 8 8 8 8 33 0.5 0.5 >32 >32 <=0.06 >3232 >32 16 8 8 8 34 0.25 0.5 >32 >32 <=0.06 8 >32 >32 32 >32 >32 32 35 88 >32 >32 <=0.06 >32 16 >32 16 32 16 16 36 0.125 0.125 >32 >32 <=0.060.125 2 16 8 8 4 4 37 0.125 <=0.06 >32 >32 <=0.06 4 >32 >32 8 16 8 8 38<=0.06 <=0.06 >32 >32 <=0.06 4 8 32 8 16 16 8 39 <=0.06 <=0.06 >32 >32<=0.06 32 8 32 16 16 16 8 40 0.125 0.125 >32 >32 <=0.06 0.125 0.5 4 4 44 4 41 <=0.06 <=0.06 >32 >32 <=0.06 16 8 >32 8 8 16 8 42 0.1250.125 >32 >32 <=0.06 32 32 >32 16 16 16 16 43 2 1 >32 >32 nd nd 32 >3216 16 16 8 44 0.5 0.125 >32 >32 <=0.06 <=0.06 16 >32 16 16 16 8 45 0.250.25 >32 >32 <=0.06 0.5 16 >32 8 8 8 4 46 <=0.06 <=0.06 >32 >32 <=0.06<=0.06 4 32 1 2 4 1 47 0.125 <=0.06 >32 >32 <=0.06 <=0.06 8 >32 4 8 4 248 0.25 0.25 >32 >32 <=0.06 >32 >32 >32 16 32 16 16 49 <=0.06<=0.06 >32 >32 <=0.06 <=0.06 2 16 4 16 4 4 50 0.25 0.125 >32 >32 <=0.0632 32 >32 8 16 8 4 51 1 1 >32 32 <=0.06 0.125 0.5 8 1 4 1 2 52 0.125<=0.06 >32 >32 <=0.06 0.125 4 8 8 16 8 8 53 0.5 0.25 >32 >32 <=0.06 116 >32 8 16 8 16 54 1 0.5 >32 >32 <=0.06 32 >32 >32 16 16 32 8 55 0.250.125 >32 >32 <=0.06 <=0.06 0.25 2 8 8 16 8 56 <=0.06 <=0.06 >32 32<=0.06 <=0.06 <=0.06 1 1 1 0.5 0.5 57 2 2 >32 >32 <=0.06 0.125 1 32 4 88 4 58 0.5 0.5 >32 >32 <=0.06 <=0.06 0.5 8 4 4 4 4 59 nd nd nd Nd nd ndnd nd nd nd nd nd 60 nd nd nd Nd nd nd nd nd nd nd nd nd ReferencesErythromycin 0.25 >32 >32 >32 <=0.06 >32 >32 >32 4 4 8 4 Clarithromycin0.125 >32 >32 >32 <=0.06 32 >32 >32 4 4 8 4

[0063] The compounds in accordance with the invention can be used asmedicaments. They possess good oral absorption properties. A furtherembodiment of the present invention are thus medicaments comprisingcompounds of formula I, their pharmaceutically acceptable acid additionsalts or in vivo cleavable esters thereof for the treatment andprevention of infectious diseases, for example, in the form ofpharmaceutical preparations for enteral (oral) administration. Theproducts in accordance with the invention can be administered, forexample, perorally, such as in the form of tablets, coated tablets,dragees, hard and soft gelatin capsules, solutions, emulsions orsuspensions, or rectally, such as in the form of suppositories, orparenterally e.g. by injection, or locally for example by topicaladministration, preferably the compounds are administered orally.

[0064] Pharmaceutical compositions containing these compounds can beprepared using conventional procedures familiar to those skilled in theart, such as by combining the ingredients into a dosage form togetherwith suitable, non-toxic, inert, therapeutically compatible solid orliquid carrier materials and, if desired, the usual pharmaceuticaladjuvants.

[0065] It is contemplated that the compounds are ultimately embodiedinto compositions of suitable oral, parenteral or topical dosage forms.The compositions of this invention can contain, as optional ingredients,any of the various adjuvants which are used ordinarily in the productionof pharmaceutical preparations. Thus, for example, in formulating thepresent compositions into the desired oral dosage forms, one may use, asoptional ingredients, fillers, such as coprecipitated aluminumhydroxide-calcium carbonate, dicalcium phosphate or lactose;disintegrating agents, such as maize starch; and lubricating agents,such as talc, calcium stearate, and the like. It should be fullyunderstood, however, that the optional ingredients herein named aregiven by way of example only and that the invention is not restricted tothe use hereof. Other such adjuvants, which are well known in the art,can be employed in carrying out this invention.

[0066] Suitable as such carrier materials are not only inorganic, butalso organic carrier materials. Thus, for tablets, coated tablets,dragees and hard gelatin capsules there can be used, for example,lactose, maize starch or derivatives thereof, talc, stearic acid or itssalts. Suitable carriers for soft gelatin capsules are, for example,vegetable oils, waxes, fats and semi-solid and liquid polyols (dependingon the nature of the active substance; no carriers are, however,required in the case of soft gelatin capsules). Suitable carriermaterials for the preparation of solutions and syrups are, for example,water, polyols, saccharose, invert sugar and glucose. Suitable carriermaterials for suppositories are, for example, natural or hardened oils,waxes, fats and semi-liquid or liquid polyols.

[0067] As pharmaceutical adjuvants there are contemplated the usualpreservatives, solubilizers, stabilizers, wetting agents, emulsifiers,sweeteners, colorants, flavorings, salts for varying the osmoticpressure, buffers, coating agents and antioxidants.

[0068] The compounds of formula I and their acid addition salts or invivo cleavable esters thereof can be used for parenteral administrationand for this purpose are preferably made into preparations for injectionas lyophilisates or dry powders for dilution with customary agents, suchas water or isotonic common salt solution.

[0069] The compounds of formula I and their acid addition salts or invivo cleavable esters thereof can be used for topical administration andfor this purpose are preferably made into preparations as ointments,cremes or gels.

[0070] For the prevention and treatment of infectious diseases inmammals, human and non-human, a daily dosage of about 10 mg to about2000 mg, especially about 50 mg to about 1000 mg, is usual, with thoseof ordinary skill in the art appreciating that the dosage will dependalso upon the age, conditions of the mammals, and the kind of diseasesbeing prevented or treated. The daily dosage can be administered in asingle dose or can be divided over several doses. An average single doseof about 100 mg, 250 mg, 500 mg and 1000 mg can be contemplated.

[0071] The compounds of the present invention can be prepared bydeacylating a compound of the general formula

[0072] wherein R¹-R³, Z and * are as above and R_(pl) is acetyl orbenzoyl, and, if desired, converting the compound of formula I obtainedinto a pharmaceutically acceptable acid addition salt or into an in vivocleavable ester thereof.

[0073] The reaction steps starting from known compounds leading to thestarting compounds of formula A and the end products of formula I arecarried out according to the following schemes 1 - 11. In the generaldiscussion and the working examples that follow, certain abbreviationsare used; those include:

[0074] TLC for thin layer chromatography;

[0075] HPLC for high performance liquid chromatography;

[0076] DMSO for dimethylsulphoxide;

[0077] DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene;

[0078] DIPEA for diisopropylethylamine (Huenig's base);

[0079] DIAD for diisopropylazadicarboxylate;

[0080] DMF for dimethylformamide;

[0081] THF for tetrahydrofuran;

[0082] DCC for dicyclohexylcarbodiimide;

[0083] DMAP for 4-dimethylaminopyridine;

[0084] EDC•HCl for N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride;

[0085] R_(f) indicates the retention of the compound on thin layerchromatography;

[0086] KO^(t)Bu for potassium tert.-butylate;

[0087] MS for mass spectrometry;

[0088] NMR for nuclear magnetic resonance;

[0089] ISP for ion spray.

[0090] The compounds of the present invention can be prepared by methodswell known in the art e.g. by chemical modification of the readilyavailable intermediate of the formula VI (scheme 1) wherein R_(p1) canbe for example acetyl, benzoyl or the like, R_(p2) acetyl, benzoyl,benzyloxycarbonyl or the like and R⁷ methyl, allyl or propargyl.Compounds of formula VI can be prepared either from erythromycin or fromclarithromycin according to published procedures.

[0091] Compounds of formula III wherein R⁷ is allyl or propargyl andR_(p1) and R_(p2) as defined above can be prepared from erythromycin bymethods described in, for example, Clark et al., Bioorg. Med. Chem.Lett. 2000, 10, 815-819 and WO 0078773. To obtain compounds of formulaIII wherein R⁷ is methyl and R_(p1) and R_(p2) as defined above the 2′-and 4″- hydroxyl groups of commercially available clarithromycin can beprotected either sequentially or simultaneously by reaction with asuitable acid anhydride or acid chloride (reaction A, scheme 1) asdescribed in, for example, Baker et al., J. Org. Chem. 1988, 53,2340-2345 and Kashimura et al., J. Antibiotics, 2001, 54, 664-678.Compounds of formula III can then be transformed into compounds offormula VI (reactions B and C) in a similar way as described in Baker etal., J. Org. Chem. 1988, 53, 2340-2345. Alternatively, compounds offormula VI with R 7=CH₃ can also be obtained by treating clarithromycin(II, R⁷=CH₃) with ethylencarbonate in refluxing triethylamine (reactionD) as described for example in Elliott et al., J. Med. Chem., 1998, 41,1651-1659 or by treating clarithromycin with ethylenecarbonate and abase such as potassium carbonate in hot DMF, preferably at 110° C. andsubsequent protection of the 2′- and 4″- hydroxyl groups by reactionwith a suitable acid anhydride in an aprotic solvent (reaction E)similar to the procedure described for example in Kashimura et al., J.Antibiotics, 2001, 54, 664-678.

[0092] Compounds of formula VI can then be ftirther reacted assummarized in scheme 2:

[0093] The hydroxy group at position 12 of compounds of formula VI isesterified by treatment with an appropriate carboxylic acid (R¹CH₂COOH),DCC and DMAP in a chlorinated solvent such as methylene chloride(reaction F¹, scheme 2). Depending on the nature of R¹ compounds offormula VIII can also be synthesised via a two step procedure where thehydroxy group at position 12 is first reacted with 2-chloro acetic acidas described above (reaction F²) to give compounds of formula VII. Theintermediate is then treated with the appropriate nucleophile R¹H inacetone in the presence of a base such as DBU (reaction G¹) to givecompounds of formula VIII. If compounds of formula VII are treated withtetrabutylammonium cyanide, compounds of formula IX wherein R¹ is cyanoare obtained directly in one step without the addition of any base.Compounds of formula VIII are treated with an alkali metal base such asNaH or potassium tert.-butoxide in a aprotic solvent such as DMF or THF(reaction H¹) to give compounds of formula IX as mixture ofdiastereoisomers in various ratios.

[0094] To prepare compounds of formula XI wherein Z=O the intermediateIX is treated with 1% to 5% HCl in an alcoholic solvent e.g. methanol orethanol, at room temperature (reaction K¹). To obtain compounds offormula XI wherein Z=NOR⁴ compounds IX are first reacted with anappropriate hydroxylamine (R⁴ONH₂) in a solvent such as ethanol,iso-propanol, butanol or pyridine at temperatures ranging from 80° C. to120° C. for 12 hours to 72 hours (reaction I) to give compounds offormula X as described for example in EP 1088828 or EP 1132392. Theseintermediates are subsequently treated as described above (reaction K²)in order to obtain compounds of formula XI wherein Z=NOR⁴. The oxidationof compounds XI is carried out with EDC*HCl, DMSO and pyridiniumtrifluoroacetate in a chlorinated solvent such as methylene chloride orusing 1,1,1-triacetoxy- 1,1-dihydro- 1,2-benziodoxol-3- (1H) -one(Dess-Martin reagent) in a chlorinated solvent such as methylenechloride to give compounds of formula XII (reaction L^(l)). Compounds offormula XII can then be further reacted according to schemes 3 and 4 ifappropriate or deprotected (for R⁷=CH₃) by stirring in an alcoholicsolvent such as methanol or ethanol for 12 to 72 hours at temperaturesranging from 20° C. to 80° C. to give free 2′-hydroxy compound offormula I as a single diastereoisomer (reaction M¹).

[0095] Where R⁷ is allyl or propargyl the group R⁵ is introduced inaccordance with process variant R¹ to yield compounds XIII by means of aso-called “Heck reaction” (for R⁷ =allyl in XII) or a so called“Sonogashira reaction” (for R⁷ propargyl in XII). In the case of the“Heck reaction” compounds of formula XIII are obtained by reacting acompound XII with compounds Lg-R⁵, where R⁵ is defined as before and Lgrepresents a leaving group, for example bromine, iodine,methanesulphonoxy, trifluoromethanesulphonoxy, benzenesulphonyloxy orp-toluenesulphonyloxy. Preferably, an inert organic solvent, e.g.dioxane, tetrahydrofuran, N,N-dimethylacetamide orN,N-dimethylformamide, is used. The reaction is preferably effected inthe presence of a base such as alkali metal carbonate, and/or a tertiaryamine, e.g. a tri(lower alkyl)amine such as triethylamine,tri-n-butylamine, diisopropylethylamine or N-ethylpiperidine, andtogether with a catalyst, preferably a palladium complex, such aspalladium(II) acetate, bis(triphenylphosphine) palladium(II)dichloride,bis(triphenyl-phosphine)palladium (II) diacetate, tetrakis(triphenylphosphine) palladium, and triphenylphosphine ortri-o-tolylphosphine, optionally with the addition of a phase transfercatalyst such as a tetraalkylammonium salt, e.g. tetrabutylammoniumbromide. The temperature of the “Heck reaction” preferably lies in theregion between about 40° C. and the boiling point of the reactionmixture.

[0096] In the case of the “Sonogashira reaction” compounds of formulaXIII are obtained by reacting a compound XII with R⁷=propargyl withcompounds Lg-R⁵, where R⁵ is defined as before and Lg represents aleaving group, for example bromine, iodine, methanesulphonoxy,trifluoromethanesulphonoxy, benzene-sulphonyloxy orp-toluenesulphonyloxy. Preferably, an inert organic solvent, e.g.dioxane, tetrahydrofuran, N,N-dimethylacetamide orN,N-dimethylformamide, is used. The reaction is preferably effected inthe presence of a base such as a secondary amine, e.g. diethylamine ordi-isopropylamine, or a tertiary amine, e.g. a tri(lower alkyl)aminesuch as triethylamine, tri-n-butylamine, dusopropyl-ethylamine orN-ethylpiperidine, and together with a catalyst, preferably a palladiumcomplex, such as palladium(II) acetate, bis(triphenylphosphine)palladium(II)dichloride, bis(triphenylphosphine)palladium (II)diacetate, tetrakis(triphenylphosphine) palladium, copper(I)iodide andtriphenylphosphine or tri-o-tolylphosphine, optionally with the additionof a phase transfer catalyst such as a tetraalkylammonium salt, e.g.tetrabutylammonium bromide. The temperature of the “Sonogashirareaction” preferably lies in the region between about 0° C. and theboiling point of the reaction mixture, preferably room temperature.

[0097] The so-obtained “Heck” and “Sonogashira” products XIII, viz.where R³⁰ is -CH₂CH=CH-R⁵ or- -CH₂C=-C-R⁵, can be saturated toR³=-(CH₂)₃-R⁵ by catalytic hydrogenation with a palladium catalyst in alower alkanol such as ethanol or in ethyl acetate at a temperaturebetween about 0° C. and 80° C., preferably at room temperature.

[0098] Deprotection of compounds XIII (reaction M²) as for reaction M¹above yields free 2′-hydroxy compounds Ia.

[0099] In scheme 3, according to reaction O, compound XII in which R¹ is-S-R_(p3) and R_(p3) is a sulfur protective group, e.g. benzyl,4-methoxybenzyl, 3,4-dimethoxybenzyl or 4-nitro-benzyl, preferably4-methoxybenzyl, and Z, Rp, and R⁷ are defined as before (compound XIIa)is treated with a sulfur-alkylating agent, preferably3-nitro-2-pyridylsulfenyl chloride in dichloromethane in the presence ofan organic acid, preferably trifluoroacetic acid, at 0° C. to roomtemperature for 20 min to 24 hours, preferably for 1 hour, to preparethe bisulfide compound XV with R_(p4) e.g. 3-nitro-2-pyridinyl. CompoundXIIa can also be treated with dimethyl(methylthio)sulfoniumtetrafluoroborate in an organic solvent like methanol, dimethylformamidor dichloromethane in the presence of traces of water at 0° C. to roomtemperature for 1 hour to 24 hours, preferably 6 hours to obtaincompound XV where Rp₄=methyl. (Analogous treatment applied for otheralkyls Rp₄).

[0100] According to reaction P, a compound of formula XV is treated witha reducing agent such as a trialkyl phosphine, preferably tributylphosphine, or a triaryl phosphine, preferably triphenyl phosphine in asolvent such as aqueous acetone, aqueous dimethyl formamide, aqueousdioxane or aqueous tetrahydrofuran, preferably aqueous dimethylformamide, at 0° C. to 60° C., preferably at room temperature for 1minute to 1 hour, preferably 15 minutes, to give compound XVI.

[0101] According to reaction Q, Compound XVI is treated, preferablywithout isolation, directly in the same solvent system as in reaction Pwith compounds of the formula Q-X-Lg, in which Q and X are defined asbefore and Lg is a leaving group, e.g. chloride, bromide, iodide,methanesulfonyloxy, p-tosylsulfonyloxy, trifluorethansulfonyloxy or avinyl group in the case where X represents a carbonyl or a sulfonylgroup. The reaction is preferably effected in the presence of a basesuch as alkali metal carbonate or hydrogen carbonate, e.g. potassiumcarbonate, cesium carbonate or sodium hydrogen carbonate, or an organicbase, e.g. triethylamine, N-ethyl N,N-diisopropylamine,1,8-diazabicyclo[5.4.0]undec-7-ene or 1,5-diazabicyclo[4.3.0]non-5-en,preferably 1,8-diazabicylo [5.4.0]undec-7-ene at temperature between 0°C. and 50° C., preferably at 20° C. It can be advantageous to addcatalytic amounts of an iodide salt, preferably sodium iodide, to thereaction mixture.

[0102] Introduction of fluorine (reaction N^(l)) at position 12 ofcompound XIIa is carried out by the methods known to the art bytreatment of XIIa with strong bases like sodium hydride, potassiumhydride, lithium diisopropylamide, lithium hexamethyldisilylamide,sodium hexamethyldisilylamide or potassium tert-butoxide, preferablysodium hydride or potassium t-butoxide, and a fluorinating agent likeN-Fluor-bis-(phenylsulfonyl)-amine or1-chloromethyl-4-fluoro-1,4-diazonia-bicyclo[2.2.2]octanebis-(tetrafluoroborate) (Selectfluor). This reaction is preferablyeffected in an inert organic solvent like diethylether, tetrahydrofuran,or dimethyl formamide, preferably dimethylformamide at temperaturebetween about −80° C. and +20° C., preferably −20° C. under an inertathmosphere.

[0103] Compounds XVII are converted into compounds lb by deprotectionreaction M³ or “Heck”/“Sonogashira” reactions R² and deprotectionreaction M⁴, this in analogy to the above reactions M^(l), R¹ and M² inScheme 2.

[0104] Compounds of formula XII wherein R¹ is CO-R_(p5) and R_(p5)represents benzyloxy, p-methoxybenzyloxy, methoxy or t-butyloxy andR_(p1), R⁷ and Z are as defined above (compounds XIIb) can be furtherelaborated as described in scheme 4. In the first step (reaction S) theester moiety is cleaved in the case of R_(p5)=benzyloxy andp-methoxybenzyloxy by treating with H₂ gas in the presence of a catalystsuch as palladium on charcoal or the like in a solvent such as ethanol,methanol, ethyl acetate, or THF at temperatures ranging from 0° C. to80° C. preferably room temperature for 1 hour to 24 hours preferably 6hours to obtain compounds of formula XIX as a mixture ofdiastereoisomers in various ratios. In the case of R_(p5)=methoxy thecompound is treated with LiOH in a mixture of water and methanol,preferably 3:1 at temperatures ranging from 0° C. to 20° C. preferably5° C. during 5 to 30 hours preferably 15 hours. In the case ofR_(p5)=t-butyloxy the compound is treated with trifluoroacetic acid inmethylene chloride at temperatures ranging from 10 to 40° C. preferably25 during 30 minutes to 5 hours preferably 2 hours or 1% to 5% HCI in analcoholic solvent such as methanol or ethanol at room temperature during1 to 24 hours, preferably 12 hours, to yield compounds of formula XIX asa mixture of diastereoisomers in various ratios (cf. T. W. Green et al.,Protective Groups in Organic Synthesis, John Wiley & Sons, 1999.)

[0105] Compounds of formula XIX are then coupled with an appropriatecompound Q-X-H wherein X has a terminal nitrogen atom using a couplingreagent such as 1,3-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl) -3-ethylcarboduimide (EDC), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-CI),O-(benzotriazol-1-yl)-N,N,N′,N′-bis(tetramethylene)uroniumtetrafluoroborate, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate, benzotriazol- 1-yloxytripyrrolidinophosphoniumhexafluorophosphate or isobutyl chloroformate in the presence of anorganic base such as triethylamine or diisopropyl ethylamine andoptionally 4-(dimethylamino)pyridine (DMAP) and/or1-Hydroxybenzotriazole (HOBT) in a solvent such as methylene chloride,acetonitrile, DMF or THF at temperatures ranging from 0° C. to roomtemperature during 1 to 24 hours to obtain compounds of formula XX as amixture of diastereoisomers in various ratios (reaction T¹). Compoundsof formula XX where R⁷=CH₃ can then be deprotected at the 2′ positionfollowing the procedure described above (reaction M⁵) to obtaincompounds of formula Ic as single diastereoisomers. In the case ofR⁷=allyl or propargyl compounds XX can be submitted to a “Heck” or“Sonogashira” reaction respectively as described above (reaction R³)yielding compounds of formula XXI. These compounds are then deprotectedas described above (reaction M⁶) to obtain compounds of formula Ic assingle diastereoisomers.

[0106] The carboxylic acid group of compounds of formula XIX whereinR⁷=CH₃, Z=O and R_(p1) is as defined above is reduced with a reducingagent such as BH₃ in a solvent such as THF at temperatures ranging from−78° C. to 25° C. during 1 hour to 24 hours preferably 3 hours (scheme5, reaction U) to give compounds of formula XXII as a mixture ofdiastereoisomer in various ratios. The hydroxy group of compounds offormula XXII is then alkylated (reaction V) analogous to the reactiondescribed in WO 0078773 with allyl t-butyl carbonate (preparationdescribed in WO 0078773) in the presence of for exampletris(dibenzylideneacetone)dipalladium and1,4-bis(diphenylphosphine)butane at temperatures ranging from 50° C. tothe boiling point of the solvent in an aprotic solvent such as THFduring 2 hours to give compounds of formula XXIII wherein X is allyl andQ is H as a mixture of diastereoisomers in various ratios.Alternatively, the hydroxy group is reacted analogous to the conditionsdescribed in Clark et al., Bioorg. Med. Chem. Lett. 2000, 10, 815-819with propargylbromide in the presence of a base such as potassiumt-butoxide potassium hydroxide or sodium hydride in a mixture of DMSOand THF at 0° C. during 1 hour to give compounds of formula XXIIIwherein X is propargyl and Q is H as a mixture of diastereoisomers invarious ratios. Compounds of formula XXIII wherein Z, R_(pl), X and Qare as defined in this paragraph, are then submitted to a “Heck”reaction in the case of X=allyl or a “Sonogashira” reaction in the caseof X=propargyl as described above (reaction R⁴) to give compounds offormula XXIV. These compounds are then deprotected at the 2′ position asdescribed above (reaction M⁸) to obtain compounds of formula Id assingle diastereoisomers.

[0107] Compounds of formula XXII can also be reacted with isocyanates ina solvent such as methylene chloride, DMF, acetonitrile or toluene,preferably in the presence of a base such as triethylamine, DBU orpyridine at temperatures ranging from 20° C to the boiling point of thesolvent during 5 to 24 hours to give compounds of formula XXIII whichare then deprotected to give compounds of formula Id as a singlediastereoisomer (reaction M⁷).

[0108] Compounds of formula XIX wherein Z=O, R⁷ is methyl, allyl orpropargyl and R_(p1) is as defined above can be further modified assummarised in scheme 6. In the first step compounds XIX are subjected tothe so called Curtius rearrangement (reaction W) by reacting withdiphenylphosphoryl azide and triethylamine in a solvent such as benzenetoluene or acetonitrile at temperatures ranging from 25° C. to theboiling point of the solvent. After 1 hour benzylalcohol,p-methoxybenzylalcohol, t-butylalcohol, 2-trimethylsilylethanol or wateris added and the mixture is heated to temperatures ranging from 50 to110° C. during 5 to 24 hours. Alternatively the same starting materialis treated with ethyl chloroformate and triethylamine in a mixture ofacetone and water at temperatures ranging from −5 to 10° C. preferably0C during 1 to 2 hours. Now sodium azide is added and the mixture isstirred for another 1 to 5 hours at the same temperature. If one of theabove mentioned alcohols has been added to the reaction mixture, thefree amine is liberated from the intermediate carbamate, depending onthe nature of the alcohol, with H₂/Pd/C (in case of benzylalcohol orp-methoxybenzylalcohol), HCl or trifluoroacetic acid (in case oft-butylalcohol) or tetrabutylammonium fluoride (in case of2-trimethylsilylethanol) according to standard procedures described inT. W. Green et al., Protective Groups in Organic Synthesis, John Wiley &Sons, 1999 to give compounds of formula XXV as a mixture ofdiastereoisomers in various ratios. If the intermediate isocyanate,which is formed during the Curtius rearrangement, is reacted withcompounds Q-XH, which have a terminal NH or OH group, compounds offormula XXVI can be formed in one step from compounds XIX (reactionW²).

[0109] Compounds XXV are coupled to appropriate carboxylic acids(reaction X^(l))under conditions described for reaction T¹, scheme 4 oralternatively to appropriate acid chlorides, chloroformate esters orsulfonyl chlorids in the presence of an amine base such astriethylamine, diisopropylethylamine or the like in a solvent such asmethylene chloride or THF at temperature ranging from −78° C. to roomtemperature during 1 hour to 24 hours to give compounds of formula XXVIas a mixture of diastereoisomers in various ratios.

[0110] Compounds of formula XXVI where R⁷=CH₃ can then be deprotected atthe 2′ position following the procedure described above (reaction M⁹) toobtain compounds of formula I as single diastereoisomers or in the caseof R⁷=allyl or propargyl compounds XXVI can be submitted to a Heck or aSonogashira reaction respectively as described above (reaction R⁵)yielding compounds of formula XXVII. These compounds are thendeprotected as described above (reaction M¹⁰) to obtain compounds offormula Ie as single diastereoisomers.

[0111] Compounds of formula XXVIII (=III) wherein R⁷ is as defined aboveand R_(pl) and R_(p2) are as defined above or H are transformed intocompounds of formula XXIX wherein R_(p2) is as defined above, but not H,following a procedure described in Elliott et al., J. Med. Chem., 1998,41, 1651-1659 (reaction Y). The hydroxy group in position 3 of compoundsXXIX is then oxidized according to the procedure described for scheme 2(reaction L²) and the product obtained then subsequently fluorinated atposition 2 following the procedure described for scheme 3 above(reaction N²) to yield compounds of formula XXXI. The hydroxy group atposition 12 of compounds of formula XXXI is then esterified to givecompounds of formula XXXIII either in a two step procedure or directlyas specified in scheme 2 above (reactions F² and G² or reaction F³).Compounds of formula XXXIII are then cyclised under similar conditionsas described in scheme 2 above (reaction H²) to give compounds offormula XXXIV as a mixture of diastereoisomers in various ratios.

[0112] Compounds of formula XXXIV can then (for R⁷=CH₃) be deprotectedat the 2′ position following the procedure described above (reactionM¹¹) to obtain compounds of formula If as single diastereoisomers, or inthe case of R⁷=allyl or propargyl compounds XXXIV can be submitted to a“Heck” or a “Sonogashira” reaction, respectively, as described above(reaction R⁶) yielding compounds of formula XXXV. These compounds arethen deprotected as described above (reaction M¹²) to obtain compoundsof formula If as single diastereoisomers.

[0113] As summarised in scheme 8. compounds of formula X)CXVI whereinR³, R_(p1), Q and X are as defined above and Y is as defined (excludingSO, SO₂ and CO) are fluorinated in the 12 position following theprocedure described above (reaction N³) to give compounds of formulaXXXVII as a mixture of diastereoisomers in various ratios. Thesecompounds are then deprotected as described above (reaction M¹³) toobtain compounds of formula Ig as single diastereoisomers.

[0114] Compounds of formula XVIII are treated with 2 to 2.5 equivalentof 3-chloroperoxybenzoic acid (MCPBA) and 4 to 5 equivalent of NaHCO₃ ina solvent such as methylene chloride at temperatures ranging from 0° C.to room temperature preferably 0° C. during 1 hour to 3 hours (reactionZ¹). The N-oxide which is formed on the dimethylamino group of the sugarresidue during the reaction is reduced at work-up by treating theorganic phase with a aqueous solution of sodium pyrosulfite at roomtemperature during 5 minutes to 24 hours to give compounds of formulaXXXVIII as a mixture of diastereoisomers. Alternatively, if appropriate,the N-oxide is reduced by catalytic hydrogenation according to standardprocedures. Compounds of formula XXXVIII can then be deprotected at the2′ position following the procedure described above (reaction M³) toobtain compounds of formula Ih as a mixture of diastereoisomers invarious ratios or are further oxidised as described above but at roomtemperature during 1 to 48 hours to give, after reduction of theN-oxide, compounds of formula XXXIX as a mixture of diastereoisomers invarious ratios (reaction Z²) Compounds XXXIX can also be obtained in onestep (reaction Z³) by using 3,5 to 10 equivalent of the oxidising agentand 7 to 20 equivalent of NaHCO₃ at temperatures ranging from 0° C. toroom temperatures during 5 to 48 hours followed by the workup proceduredescribed above. Compounds of formula XXXIX are then deprotected at the2′ position following the procedure described above (reaction M¹⁵) toobtain compounds of formula Ii as single diastereoisomers.

[0115] In the case where Q is further substituted with oxidationsensitive substituents like amino groups, these substituents need to beprotected before submitting the sulfide XVIII to oxidation. Suitableprotecting groups commonly known in the art can be introduced accordingto standard procedures described in T. W. Green et al., ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1999. After oxidation(reaction Z¹, Z² or Z³), the protecting group can be removed followingstandard procedures also described in T. W. Green et al.

[0116] Compounds of formula XXII, triphenylphosphine and HN₃ aredissolved in a solvent such as benzene or THF and treated with diethylazodicarboxylate at temperatures ranging from −78° C. to roomtemperature during 1 to 24 hours. Another equivalent oftiphenylphosphine is added followed after 3 to 24 hours by water ordilute hydrochloric acid at temperatures ranging from 20° C. to 50° C.(reaction AA) to give compounds of formula XL as a mixute ofdiastereoisomers in various ratios. Compounds of formula XL are thenfurther modified (reaction X²) according to the procedure described inX¹ to give compounds of formula XLI as a mixture of diasteroisomers invarious ratios. Compounds of formula XLI can then be deprotected at the2′ position following the procedure described above (reaction M¹⁶) toobtain compounds of formula Ij as single diastereoisomers, or in thecase of R⁷=allyl or propargyl compounds XLI can be submitted to a “Heck”or a “Sonogashira” reaction, respectively, as described above (reactionR⁷) yielding compounds of formula XLII. These compounds are thendeprotected as described above (reaction M¹⁷) to obtain compounds offormula Ij as single diastereoisomers.

[0117] Compounds of formula XLIII wherein R⁷ and Rp₁ are as describedabove and Rp₆ is an amino protecting group like t-butoxy carbonyl(t-BOC), benzyloxycarbonyl (Z) or allyloxycarbonyl (Alloc),preferentially t-butoxy carbonyl, are obtained following the proceduredescribed in scheme 2 using N-protected 2-aminoethane thiol in reactionG. Compounds of formula XLIII are transformed into compounds of formulaXLV by cleavage of the amino protecting group Rp₆. The amino protectinggroups may be cleaved off by acid hydrolysis (e.g. the t-butoxycarbonylgroup), preferably with the aid of a lower alkanecarboxylic acid whichmay be halogenated. In particular formic acid or trifluoroacetic acid isused. The reaction is carried out in the acid or in the presence of aco-solvent such as a halogenated lower alkane, e.g. methylene chloridepreferably at room temperature although it can be carried out at aslightly lower or a slightly higher temperature (e.g. a temperature inthe range of about −30° C. to +40° C.). The benzyloxycarbonyl group canbe cleaved off by hydrogenation at atmospheric pressure in the presenceof a catalyst, e.g. Palladium on charcoal in a solvent like ethanol,methanol or ethyl acetate. The allyloxycarbonyl group is cleaved in apalladium (0) catalysed transallylation in the presence of an allylgroup scavenger such as, e.g. trimethylsilanyldimethylamine, asdescribed in Tetrahedron Letters, 33, 477,-480 (1992). Alternatively,compounds of formula XLIII can first be oxidised into compounds offormula XLIV as described for scheme 9. Compounds of formula XLIV aresubsequently transformed into compounds of formula XLV followingprocedures described above. Crude compounds of formula XLV are coupledto appropriate carboxylic acids (reaction AC) under conditions describedfor reaction T¹, scheme 4 or alternatively to appropriate acidchlorides, chloroformate esters or sulfonyl chlorides as described forreaction XI, scheme 6 to give compounds of formula XII. Alternativelycompounds of formula XII can be obtained by conducting a nucleophilicaromatic substitution of halogenated aromatic or heteroaromaticderivatives with compounds of formula XLV in a protic solvent likeethanol or methanol at temperatures between 20° C and refluxingtemperature, during 1 to 48 hours in the presence of an organic basesuch as triethylamine. The substitution can also be conducted in a polaraprotic solvent like N,N-dimethylformamide, N,N-dimethyl acetamideN-methyl pyrrolidone or acetonitrile at temperature ranging from 20° C.to 150° C. during 1 to 24 hours. The cross coupling can also becatalysed by Pd (O) complexes following the procedures described forexample in J. Org. Chem. 1996, 61, 7240-7241.

[0118] Compounds XII are then deprotected as described above (reactionM¹) to obtain compounds of formula Ik as single diastereoisomers.Compounds XII can be further transformed by submitting them to a Heck orShonogashira reaction as described above (reaction R¹ scheme 2). Finalproducts of formula Ik are then deprotected as described above (reactionM¹).

[0119] “Heck” and “Sonogashira” products XVIII, XXI, XXIII, XXVII, XXXVand XLII can be saturated in analogy to compounds XIII as describedabove.

[0120] The following Examples illustrate the invention without beingconstrued as limiting.

EXAMPLE 1

[0121] Preparation of (3R or S, 3aR, 4R or S, 6R, 8R, 9R, IOR, 12S, 15R,15aS)-15-Ethyl-12-fluorooctahydro-8-methoxy-3- [[(4-methoxyphenyl)methyl]thio]-4,6,8,10,12,15a-hexamethyl-9-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-2H-furo[2,3-c] oxacyclotetradecin-2,5,11,13 (3H,6H,12H)-tetrone (I-1), compoundof formula I, wherein R¹ is [(4-methoxyphenyl) methyl]thio, R² isfluoro, R³,is methyl and Z is oxygen. A] (1OE)- 10,11-Didehydro- 11-deoxy-6-O-methyl-erythromycin 2′-acetate 12-(chloroacetate)4″-(phenylmethyl carbonate) (VII-1) (Scheme 2, formula VII):

[0122] To a solution of 14 g (15.4 mmol)(10E)-10,11-didehydro-11-deoxy-6-0-methyl-erythromycin-2′-acetate-4″-(phenylmethylcarbonate) (VI) and 566 mg DMAP in 280 ml dichloromethane, were addedsimultaneously a solution of 4.38 g (46.35 mmol) of chloroacetic acid in70 ml dichloromethane and a solution of 9.56g (46.35 mmol) DCC in 70 mlCH₂Cl₂ dropwise over 2 hours under argon. Following addition, thesolution was stirred a room temperature for further 2 hours. The volumeof the reaction mixture was reduced under reduced pressure to 100 ml andthe insoluble precipitate was eliminated by filtration. The filtrate waswashed twice with 50 ml of a 5% aqueous NaHCO₃ solution. The organiclayer was washed successively with 50 ml water, 50ml brine, dried overNa₂SO₄ and evaporated. The resulting oil was purified by flashchromatography (1% NH₃OH in dichloromethane/MeOH 90:10). Fractionscontaining pure product were combined, evaporated and dried underreduced pressure to give 15 g (98%) product as a colorless foam. MS(ISP): 982.4 (MH⁺).¹H-NMR (CDCl₃) diagnostic signals only: 0.90 (t, 3H),0.93 (d, 3H), 1.12 (d, 3H), 1.18 (d, 3H), 1.24 (s, 3H), 1.28 (d, 3H),1.35 (d, 3H), 1.70 (s, 3H), 2.00 (s, 3H), 2.23 (s, 6H), 2.40 (d, 1H),2.67 (m, TH), 2.87 (m ,TH), 3.12 (s, 3H), 3.24 (m, 1H), 3.32 (s, 3H),3.56 (m, 2 H), 3.81 (m, 1H), 3.98 (s, 2H), 3.86 (m, IH), 3.95 (d, 1H),4.07 (d, 1H), 4.29 (m, IH), 4.96 (m, 1H), 5.21 (dd, 2H), 5.71 (dd, 1H),6.60 (s, 1H), 7.35 (s, 5H).

[0123] B] (10E)-10,11-Didehydro-11-deoxy-6-O-methyl-erythromycin2′-acetate 4Δ-(phenylmethyl carbonate)12-[[[(4-methoxyphenyl)methyl]thio]acetate] (VIII- 1):

[0124] To a solution of 10 g (10.1 mmol) VII-1 dissolved in 400 mlacetone were added 1.74 g (11.4 mmol) DBU and a catalytic amount ofsodium iodide. (4-Methoxyphenyl)-methanethiol (1.66g, 10.78 mmol) wasadded in one portion and the resulting suspension was stirred at roomtemperature for 1.5h. The reaction mixture was diluted with 1 I CH₂Cl₂,extracted twice with 400 ml 5% aqueous NaHCO₃, dried over Na₂SO₄ andevaporated to give 10.55 g of a foamy beige compound. The crude productwas used without purification for the next step. MS (ISP): 1100.6 (MHN).

[0125] C] (3R or S, 3aR, 4R or S, 6R, 8R, 9R, 1OS, 1lS, 12R, 15R,15aS)-9-[[2-O-Acetyl-3,4,6-tri-deoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-11-[[2,6-dideoxy-3-C-methyl-3-O-methyl-4-O-[(phenylmethoxy)carbonyl]-α-L-ribo-hexopyranosyl]oxy]-15-ethyl-decahydro-8-methoxy-3-[[(4-methoxyphenyl)methyl]thio]-4,6,8,10,12,15a-hexamethyl-2H-furo[2,3-c] oxacyclotetradecin-2,5,13 (3H,6H)-trione; mixture ofdiastereomers (IX-1):

[0126] To an ice cold solution of 3 g (2.72 mmol) of ester VIII-1 in 30ml dry DMF kept under argon was added at once 164 mg of a 60% sodiumhydride oil dispersion. The resulting mixture was stirred at 0° C. for 3hours and then partitioned between 50 ml diethylether and 50 ml of 0.5 MKH₂PO₄ solution. The organic layer was washed twice with 50 ml of 3%NaHCO₃ solution and 50 ml brine, dried over Na₂SO₄ and evaporated toyield 2.97 g of crude product as a yellow foam. MS (ISP): 1100.6 (MH+)

[0127] D](3R orS, 3aR, 4R orS, 6R, 8R, 9R, lOS, I IS, 12R, 15R,15aS)-9-[[2-O-Acetyl-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-15-ethyldecahydro-11-hydroxy-8-methoxy-3-[[(4-methoxyphenyl)methyl]thio]-4,6,8,10,12,15a-hexamethyl-2H-furo[2,3-c] oxacyclotetradecin-2,5,13 (3H,6H)-trione; mixture ofdiastereomers (XI-1):

[0128] 2.96 g (2.69 mmol) IX-1 were dissolved in 150 ml methanolcontaining 3% HCl. The solution was kept at room temperature for 24hours and evaporated. The crude hydrochloride salt was redissolved in100 ml dichloromethane, washed twice with 50 ml 5% NaHCO₃ and 50 mlbrine, dried over Na₂SO₄ and evaporated to give 2.8 g of crude productwhich was purified by chromatography on silica gel eluting withdichloromethane/methanol 9:1 to give 1.52 g of a colorless foam. MS(ISP): 808.5 (MH⁺).

[0129] E] (3R or S, 3aR, 4R or S, 6R, 8R, 9R, 10R, 12R, 15R, 15aS)-9-[[2-O-Acetyl-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-15-ethyloctahydro-8-methoxy-3- [[(4-methoxyphenyl)methyl]thiol-4,6,8,10,12,15a-hexamethyl-2H-furo [2,3-cloxacyclo-tetradecin-2,5,11,13 (3H,6H, 12H) -tetrone; mixture ofdiastereomers (XII-1):

[0130] 19.6 g of a 15% wt solution of Dess-Martin reagent indichloromethane was added dropwise over a period of 10 minutes to asolution of 1.5 g (2.69 mmol) XI-1 in 130 ml dichloromethane at 0° C.under argon. The reaction mixture was stirred at 0° C. for 1h30 and atroom temperature for 1 h. The resulting yellow solution was diluted with25 ml diethyl ether and then poured into a mixture of 148 g of a 10%aqueous solution of Na₂S₂O₃ and 13.5 g of a saturated NaHCO₃ solutionand stirred for 1h. The organic layer was separated, the aqueous phasewas extracted twice with 100 ml of diethylether. The combined organicphases were washed with 100 ml of 3% NaHCO₃, 100 ml water, 100 ml brine,dried over Na₂SO₄ and evaporated. Flash chromatography on silica gelwith dichloromethane/methanol/ammonia 90:10:1 gave 1.34 g (61%) of theprotected ketolide XII-1 as a beige foam as a mixture of diastereomers.MS (ISP): 806.6 (MH⁺).

[0131] F] (3R orS, 3aR, 4R orS, 6R, 8R, 9R, lOR, 12S, 15R,15aS)-9-[[2-O-Acetyl-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-15-ethyl-12-fluoroctahydro-8-methoxy-3-[[(4-methoxyphenyl)methyl]thio]-4,6,8,10,12,15a-hexamethyl-2H-ftiro[2,3-c]oxacyclo-tetradecin-2,5,11,13 (3H,6H,12H)-tetrone; (XIV-1)

[0132] To a solution of 200 mg (0.248mmol) of ketolide XII- 1 in 3 mlDMF at 0° C. under argon was added sodium hydride (60% in oil, 21.8 mg,0.546 mmol) and the mixture was stirred at 0° C. for 1 h. To this orangesolution cooled to −20° C. was added N-fluoro-benzenesulfonimide (86.1mg, 0.27mmol) and the mixture was stirred at 0° C. for 5 min. Thereaction mixture was then treated dropwise with a solution of 30 mgacetic acid in 0.7 ml DMF over a period of 10 min., diluted with 50 mlEthyl acetate and washed twice with 25 ml of a 3% aqueous NaHCO₃solution and with 35 ml brine, dried over Na₂SO₄ and evaporated. Thecrude product was purified by chromatography on silica gel withdichloromethane/methanol/ammonia 95:5:1 to give 40 mg (20%) of thedesired compound XIV-1 as a slightly yellow foam. MS (ISP): 824.2 (MH+)and 145 mg (70%) of the N-oxide derivative of XIV-1 MS (ISP): 840.2(M⁺).

[0133] G] (3R or S, 3aR, 4R or S, 6R, 8R, 9R, IOR, 12S, 15R,15aS)-15-Ethyloctahydro-12-fluoro-8-methoxy-3-[[(4-methoxyphenyl)methyl]thio]-4,6,8,10,12,15a-hexamethyl-9-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-2H-furo[2,3-c] oxacyclotetradecin-2,5,11,13 (3H,6H, 1 2H) -tetrone (I-1):

[0134] 230 mg of protected ketolide XIV-1 were dissolved in 5 mlmethanol and stirred for 72 hours at room temperature. The solvent wasremoved under reduced pressure. The residue was dissolved in 10 mldichloromethane and the resulting solution stirred with 10 ml of a 10%aqueous solution of sodium pyrosulfite during 1h. The pH of the solutionwas set on pH 8 with a saturated solution of NaHCO₃ and the organicphase separated. The aqueous phase was extracted twice with 10 mldichloromethane and the combined organic phases were dried over Na₂SO₄and evaporated. The crude product was purified by chromatography onsilica gel eluting with dichloromethane/methanol/ammonia 90:10:1 to give111 mg (51%) of the desired compound I-1 as a single diastereomer. MS(ISP): 782.3 (MH⁺). ¹H-NMR (CDCl₃) diagnostic signals only: 0.91 (t,3H), 1.04 (d, 3H), 1.13 (d, 3H), 1.27 (d, 3H), 1.29 (d, 3H), 1.31 (s,3H), 1.51 (s, 3H), 1,6-1,7 (m),22H), 1.78 (d, 3H), 2.26 (s broad, 6H),2.64 (s, 3H), 2.98 (q, 1H), 3.31 (m, 1H), 3.56 (m, 2H), 3.80 (s, 3H),4.06 (dd, 2H), 4.37 (d, 1H), 5.42 (dd, 1H), 6.83 (d, 2H), 7.32 (d, 2H).

EXAMPLE 2

[0135] Preparation of 1-2, compound of formula I, where R¹ is[(4-methoxyphenyl)methyl]-sulfonyl, R² is fluoro, R³ is methyl and Z isoxygen.

[0136] A] To a stirred solution of 65 mg (79 umol) sulfide XVIII-1 in 3ml dichloromethane at 0° C. were added 46 mg (550 μmol) of sodiumbicarbonate and 68 mg (276 μmol) of m-chloroperbenzoic acid. The mixturewas allowed to warm to room temperature and stirred for 2 h. 5 ml of anaqueous sodium pyrosulfite solution were added and the two-phase systemwas stirred for 1 h. The pH of the solution was adjusted to pH 9 withsaturated sodium carbonate solution and extracted twice with 10 mldichloromethane. The combined organic phases were washed with 10 ml 3%NaHCO₃ aqueous solution, 10 ml of brine, dried over Na₂SO₄ andevaporated to give 55 mg (81%) of compound XXXIX-2 as a light yellowsolid. MS (ISP): 856.3 (MH⁺).

[0137] Deprotection of XXXIX-2 was performed as described in example 1Gto give product I-2 as a colorless solid as a single diastereomer. MS(ISP): 814.3 (MH⁺). ¹H-NMR (CDCl₃) diagnostic signals only: 0.94 (t,3H), 1.03 (d, 3H), 1.12 (d, 3H), 1.24 (d, 3H), 1.28 (s, 3H), 1.30 (d,3H), 1.61 (s, 3H), 1,55-1,75 (m, 2H), 1.74 (d, 3H), 2.26 (s, 6H), 2.63(s, 3H), 3.05-3.20 (m, 3H), 3.46 (m, 1H), 3.62 (m, 1H), 3.80 (s, 3H),4.06 (d, 1H), 4.61 (dd, 2H), 5.53 (dd, 1H), 6.91 (d, 2H), 7.46 (d, 2H).

EXAMPLE 3

[0138] Preparation of 1-3, compound of formula I, where R¹is(3-nitro-2-pyridinyl)dithio, R² is hydrogen, R³ is methyl and Z isoxygen.

[0139] [A] (3R or S, 3aR, 4R or S, 6R, 8R, 9R, lOR, 12R, 15R,15aS)-9-[[2-O-Acetyl-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-15-ethyloctahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-3-[(3-nitro-2-pyridinyl)dithioj -2H-furo [2,3-c]oxacyclo-tetradecin-2,5,11,13 (3H,6H,12H)-tetrone; (XV-3)

[0140] To a solution of compound XII-1 (1 g, 1.24 mmol) in 25 mldichloromethane at room temperature was added3-nitro-2-pyridinesulfenylchloride (0.473 g, 2.48 mmol) andtrifluoroacetic acid (0.285 ml, 3.72 mmol). The reaction mixture wasstirred at room temperature for 1 h. The deeply red colored mixture wastaken up with 50 ml dichloromethane and washed with 40 ml aqueous 3%NaHCO₃, 40 ml water and 40 ml brine, dried over sodium sulfate andevaporated. Chromatography of the crude product on silica gel elutingwith a gradient of 0 to 10% methanol/ammonium hydroxyde 9:1 indichloromethane gave the title compound as a greenish foam. MS (ISP):840.3 (MH+).

[0141] Deprotection of XV-3 was performed as described in example IG togive product I-3 as a greenish foam as a single diastereomer. MS (ISP):798.3 (MH⁺). ¹H-NMR (CDCl₃) diagnostic signals only: 1.02 (t, 3H), 1.05(d, 3H), 1.16 (d, 3H), 1.24 (d, 3H), 1.34 (s, 3H), 1.38 (d, 3H), 1.54(s, 3H), 1,55-1,75 (m, 2H), 2.26 (s, 6H), 2.79 (s, 1H), 2.86 (s, 3H),3.05-3.20 (m, 3H), 3.46 (m, 1H), 3.55 (m, 1H), 3.89 (q, 1H), 4.28 (d,1H), 4.34 (d, 1H), 5.91 (dd, 1H), 7.33 (dd, 1H), 8.49 (d, 1H), 8.83 (d,1H).

EXAMPLE 4

[0142] Preparation of (3R or S, 3aR, 4R or S, 6R, 8R, 9R, lOR, 12R, 15R,15aS)-3- [[2-(2-amino-quinolin-8-yl)2-oxoethyl]-thio]-15-ethyloctahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-9-[[-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-2H-furo[2,3-c]oxacyclotetradecin-2,5,11,13 (3H,6H,12H)-tetrone (1-4) compoundof formula I, where R¹ is [2-(8-quinolinylamino)-2-oxoethyl]thio, R² ishydrogen, R³ is methyl and Z is oxygen.

[0143] To a solution of 30 mg (36 μmol) of compound XV-3 in 1 ml DMF and0.05 ml water under argon at room temperature was added 7,2 mg (36 μmol)tributyl phosphine and the reaction mixture was stirred for 15 min. A MSspectrum of an aliquot of the reaction mixture shows the presence of theunstable thiol XVI, where R² is hydrogen, R⁷ is methyl, Rp₁ is acetyland Z is oxygen (scheme 3). MS (ISP): 686.2 (MH⁺). The mixture was thentreated sequentially with 2 mg sodium iodide, 25 mg (71 μmol)2-bromo-N-quinolin-8-yl-acetamide and 21.7 mg DBU (143 μmol) and stirredfor 30 min. at room temperature. The solvents were evaporated underreduced pressure at 30° C. and the crude residue dissolved in 3 mlmethanol and stirred for 72 h at room temperature. The solution wasconcentrated under vacuum at 30° C. and the residue purfied by HPLCRP-C18 with a gradient of 10 to 50% acetonitrile in water/formic acid99.5:0.5 to give 17.6 mg (59%) of the title compound as a slightly beigeamorphous compound as a single diastereomer. MS (ISP): 828.4 (MH⁺).¹H-NMR (CDCl₃) diagnostic signals only: 0.89 (t, 3H), 1.09 (2d, 6H),1.26 (s, 3H), 1.32 (d, 3H), 1.40 (d, 3H), 1.51 (s, 3H), 1,55-1,80 (m,3H), 1.94 (m, 1H), 2.35 (s, 6H), 2.50 (m, 1H), 2.69 (s, 11H), 2.83 (s,3H), 3.00- 3.30 (m, 3H), 3.58 (m, 1IH), 3.82 (d, 1IH), 3.84 (q, 11H),4.06 (s, 1H), 4.09 (s, 1H), 4.25 (d, 1H), 4.35 (s, 1H), 4.50 (s, 1H),5.58 (dd, 1H), 7.41 (m, 1H), 7.51 (m, 2H), 8.12 (dd, 1H), 8.79 (m, 1H),8.81 (1H).

EXAMPLE 5

[0144] Preparation of I-5 compound of formula I, where R¹ is[2-methoxy-2-oxoethyl]-thio, R² is hydrogen) R³ is methyl and Z isoxygen.

[0145] The title compound was prepared according to example 4 startingfrom XV-3 and bromoacetic acid methyl ester. MS (ISP): 716.3 (MH⁺).¹H-NMR (CDCl₃) diagnostic signals only: 0.86(t, 3H), 0.98 (d, 3H), 1.16(d, 3H), 1.32 (d, 3H), 1.35 (s, 3H), 1.51 (s, 3H), 1,55-1,80 (m, 3H),1.94 (m, 1H), 2.38 (s) 6H), 2.60 (s, 1H), 2.79 (s, 3H), 3.00- 3.30 (m,3H), 3.80 (s, 3H), 3.82 (q, 1H), 4.26 (d, 1H), 4.37 (d, 1H), 4.54 (s,1H), 5.53 (dd, 1H).

EXAMPLE 6

[0146] Preparation of 1-6 compound of formula I, where R¹ is[2-(3,4-dihydro-1H-2-oxo-quinolin-6-yl)-2-oxoethyl]thio, R² is hydrogen,R³ is methyl and Z is oxygen.

[0147] The title compound was prepared according to example 4 startingfrom XV-3 and 6-(2-bromo-acetyl)-3,4-dihydro-1H-quinolin-2-one. MS(ISP): 831.2 (MH1). ¹H-NMR (CDCl₃) diagnostic signals only: 0.91(t, 3H),1.11 (d, 3H), 1.15 (d, 3H), 1.25 (s, 3H), 1.31 (d, 3H), 1.38 (d, 3H),1.51 (s, 3H), 1,55-1,80 (m, 3H), 1.94 (m, 1H), 2.39 (s, 6H), 2.65 (s,3H), 2.90-3.10 (m, 4H), 3.24 (m, 1H), 3.82 (q, 1H), 4.26 (d, 1H), 4.29(d, 1H), 4.34 (s, 1H), 4.40 (s, 1H), 5.58 (dd, 1H), 6.76 (d, 1H), 7.78(m, 1H), 7.84(d, 1H), 7.88 (s, 11H).

EXAMPLE 7

[0148] Preparation of 1-7 compound of formula I, where R¹ is[2-oxo-2-(pyridin-2-yl)ethyl]thio, R² is hydrogen, R³ is methyl and Z isoxygen.

[0149] The title compound was prepared according to example 4 startingfrom XV-3 and 2-bromo-1-pyridin-2-yl-ethanone. MS (ISP): 763.2 (MH⁺).¹H-NMR (CDCl₃) diagnostic signals only: 0.89(t, 3H), 1.11 (d, 3H), 1.21(s, 3H), 1.25 (d, 3H), 1.31 (d, 3H), 1.38 (d, 3H), 1.51 (s, 3H),1,55-1,80 (m, 3H), 1.95 (m, 1H), 2.31 (s, 6H), 2.48 (s, 3H), 2.61 (s,IH), 3.01 (m, 1H), 3.11 (m, 1H), 3.20 (m, 1H), 3.55 (m, 1H), 3.82 (q,1H), 4.21 (d, 1H), 4.32 (d, 1H), 4.34 (s, 1H), 4.40 (d, 1H), 4.46 (s,IH), 4.63(d, 1H), 5.49 (dd, 1H), 7.41 (m, 1H), 7.83 (m, 1H), 8.21(d,1H), 8.61 (m, 1H).

EXAMPLE 8

[0150] Preparation of 1-8 compound of formula I, where R¹ is3-[3-oxo-3-(1,2,3,4-tetrahydro-isoquinolin-2-yl)propyl]thio, R² ishydrogen, R³ is methyl and Z is oxygen.

[0151] The title compound was prepared according to example 4 startingfrom XV-3 and 1,2,3,4-tetrahydro-2-(1-oxo-2-propenyl)-isoquinoline. MS(ISP): 831.3 (MH+). 1H-NMR (CDCl₃) diagnostic signals only: 0.87(t, 3H),1.11 (d, 3H), 1.14 (d, 3H), 1.25 (s, 3H), 1.28 (d, 3H), 1.31 (d, 3H),1.38 (d, 3H), 1.51 (s, 3H), 1,55-1,80 (m, 3H), 1.95 (m, 1H), 2.27 (s,6H), 2.63 (s, 1H), 2.69 (s, 3H), 2.70-3.30 (m, 6H), 3.48 (m, 1H),3.70-3.90 (m, 6H), 4.22 (m, 1H), 4.42 (d, 1H), 4.70 (m, 4H), 5.41 (dd,1H), 7.10-7.20 (m, 4H).

EXAMPLE 9

[0152] Preparation of 1-9 compound of formula I, where R¹ is 3-[ [[2-(6-amino-9H-purin-9-yl)ethyl]methylamino]-ethyl]thio, R² is hydrogen,R³ is methyl and Z is oxygen.

[0153] A][[2-(6-amino-9H-purin-9-yl) ethyl] methylamino]-ethanol

[0154] 0.6 g (3 mmol) 9-(chloroethyl)-6-amino-9H-purine (Chemistry ofHeterocyclic Compounds, 1996, 32, 333-337) was dissolved in 10 mln-butanol and treated with 0.684 g (9 mmol) of N-methylaminoethanol at110° C. for 18 h. The solvent was evaporated under reduced pressure andthe crude mixture purified by flash chromatography on silica gel with agradient of 0 to 25% methanol in dichloromethane to yield 0.68 g (94%)of a light orange solid. MS (ISP): 237.3 (MH⁺).

[0155] B] Ethanethioic acid, S-[2-[(6-amino-9H-purin-9-yl)ethyl]methylamino]ethyl]ester

[0156] Diisopropylazodicarboxylate (0.829g, 4.1 mmol) was added dropwiseto a solution of 1.075 g (4.1 mmol) triphenylphosphine in 20 ml THF keptat 0° C. The mixture was stirred for 30 minutes and then a solution of0.473 g (2 mmol) of [ [2-(6-amino-9H-purin-9-yl)ethyl]methylamino]-ethanol and 0.312 g thioacetic acid (4.1 mmol) in 20ml THF was added. The reaction mixture was stirred at 0° C. for 2 h andovernight at RT. After evaporation under reduced pressure, the residuewas purified by flash chromatography on silica gel with a gradient of 0to 20% methanol in dichloromethane. 0.547 g (92%) of a light yellowproduct was isolated. MS (ISP): 295.4 (MH⁺).

[0157] C] [[2-(6-amino-9H-purin-9-yl)ethyll methylamino]-1-ethanethiol:

[0158] 0.27 g (0.92 mmol) ethanethioic acid,S-[2-[(6-amino-9H-purin-9-yl)ethyl]methyl-amino]ethyl]ester wassuspended in 10 ml degassed methanol, kept under argon. Ammonia wasbubbled through the solution for 5 minutes and the internal temperaturerose to 40° C. The resulting solution was stirred for 60 minutes, thenconcentrated and the crude product was dried at 60° C. in vacuo. Yield:210 mg (90%). MS (EI): 253.4 (MH⁺).

[0159] The title compound (1-9,) was prepared according to example 1,steps B-E and G starting from [[2-(6-amino-9H-purin-9-yl)ethyl]methylamino]-1-ethanethiol and VII-1. MS (ISP): 862.5 (MH⁺).¹H-NMR (CDCl₃) diagnostic signals only: 0.89(t, 3H), 1.11 (d, 3H), 1.15(d, 3H), 1.27 (s, 3H), 1.28 (d, 3H), 1.31 (d, 3H), 1.40 (d, 3H), 1.52(s, 3H), 1,55-1,80 (m, 3H), 1.95 (m, 1H), 2.26 (s, 6H), 2.31 (s, 3H),2.63 (s, 1H), 2.75 (s, 3H), 2.70-2.90 (m, 2H), 3.02-3.25 (m, 3H),3.40-3.60 (m, 4H), 3.84 (q, 1H), 4.25-4.40 (m, 4H), 5.41 (m, 2H), 5.49(dd, 1H), 8.03 (s, 1H), 8.36 (s, 1H).

EXAMPLE 10

[0160] Preparation of 1-10, compound of formula I wherein R¹ is[3-(4-phenyl-lH-pyrazol-1-yl)-propyllthio, R² is fluoro, R³ is methyland Z is oxygen.

[0161] A]1-(3-chloroprop-1-yl)-4-iodo-1H-pyrazole

[0162] 2.0 g (10.31 mmol) 4-iodopyrazole were dissolved in 20 ml DMF and1.22 g (10.8 mmol) potassium t-butoxide was added. The mixture wasstirred for 1 hour at room temperature and 1.06 ml (10.83 mmol)1-bromo-3-chloropropane were added. A white precipitate appearedrapidly. After 30 minutes 50 ml water was added and the reaction mixturewas extracted twice with 100 ml hexane. The combined organic layers weredried over MgSO₄ and the solvent was removed to give 2.65 g of thedesired product as a colourless oil. MS (ISP): 270.1 (MH⁺). ¹H-NMR(CDC1₃): 2.31 (quint, 2H), 3.47 (t, 2H), 4.32 (t, 2H), 7.48 (s, 1H),7.53 (s, 1H).

[0163] B]1 -(3-chloroprop- 1 -yl)-4-phenyl- 1H-pyrazole

[0164] To a solution of 0.50 g (1.85 mmol)1-(3-chloroprop-1-yl)-4-iodo-1H-pyrazole in 10 ml dioxane 0.34 g (2.78mmol) phenylboronic acid, 0.107 g (0.09 mmol)tetrakis(triphenylphosphine)-palladium(0) and 3 ml of an aqueous 2MK₃PO₄ solution were added and the solution was degassed 3 times andheated to 60° C. for 3 hours under an atmosphere of argon. 100 ml ofwater were added and the mixture was extracted twice with ethyl acetate.The combined organic layers were dried over Na₂SO₄ and evaporated underreduced pressure. The residue was purified by flash chromatography onsilica gel (first hexane/ethyl acetate 8:2 then ethyl acetate) to give233 mg of the desired product as yellow crystals.MS (ISP): 221.3 (MH⁺).¹H-NMR (CDCl₃): 2.36 (quint, 2H), 3.50 (t, 2H), 4.35 (t, 2H), 7.25 (m,1H), 7.39 (m, 1H), 7.47 (m, 1H), 7.68 (s, 1H), 7.80 (s, 1H).

[0165] C]Ethanethioic acid, S-[(4-phenyl-1H-pyrazol-1-yl)propyl]ester

[0166] 0.23 g (1.04 mmol) 1-(3-chloroprop-1-yl)-4-phenyl-1H-pyrazolewere dissolved in 6 ml acetone, potassium thioacetate (0.15 g, 1.3 mmol)was added and the mixture was heated to reflux during 16 hours. Thesolvent was evaporated under reduced pressure and the residue wvaspurified by flash chromatography on silica gel (hexane/ethyl acetate,gradient 9:1 to 7:3) to give 240 mg of the desired product as a yellowoil. MS (EI): 260.1 (M⁺). ¹H-NMR (CDCl₃): 2.19 (quint, 2H), 2.35 (s,3H), 2.87 (t, 2H), 4.21 (t, 2H), 7.23 (m, 1H), 7.36 (m, 1H), 7.47 (m,lH), 7.64 (s, IH), 7.78 (s, 1H).

[0167] D]3-(4-phenyl-1H-pyrazol- 1-yl)propanethiol

[0168] 240 mg (0.92 mmol) ethanethioic acid,S-[(4-phenyl-1H-pyrazol-1-yl)propyl] ester were dissolved in 10 mldegassed methanol kept under argon. Dry ammonia was bubbled through thesolution during 5 minutes and the temperature rose to approx. 40° C. Theresulting solution was stirred for 1 hour and subsequently evaporatedand dried in vacuo. The crude product was used immediately for the nextreaction. MS (ISP): 219.2 (MH⁺). The title compound 1-10 was preparedstarting from 3-(4-phenyl-1H-pyrazol-1-yl)propanethiol and VII-1according to example 1 steps B-G. MS (ISP): 846.4 (MH⁺).

EXAMPLE 11

[0169] Preparation of I-11, compound of formula I wherein R¹ is[3-(4-phenyl-1H-pyrazol-1-yl)-propyl]sulfonyl, R² is fluoro R³ is methyland Z is oxygen.

[0170] The title compound was prepared from the product of example 10step E following the procedures described in example 2 step A and inexample 1 step G. MS (ISP): 878.4 (MH⁺). ¹H-NMR (CDCl₃) diagnosticsignals only: 0.94 (t, 3H), 1.10 (d, 3H), 1.15 (d, 3H), 1.23 (d, 3H),1.26 (s, 3H), 1.28 (s, 3H), 1.31 (d, 3H), 1.81 (s, 3H), 1.86 (s, 3H),2.29 (s, 6H), 2.67 (s, 3H), 3.10 (s,lH), 3.17 (m, 3H), 3.44 (m, 4H),3.63 (m, 2H), 4.10 (d, 1H), 4.32 (d, 1H), 4.39 (m, 3H), 4.71 (s, 1H),5.51 (dd, 1H), 7.21 (m, 1H), 7.35 (t, 2H), 7.49 (d, 2H), 7.74 (s, 1H),7.79 (s, 1H).

EXAMPLE 12

[0171] Preparation of (3R or S, 3aR, 4R or S, 6R, 8R, 9R, lOR, 12S, 15R,15aS)-15-Ethyl-12-fluorooctahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-3-[[2-[3-(3-pyridinyl)- 1H-1,2,4-triazole- 1-yl]ethyl]thio]-9-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-2H-furo[2,3-c] oxacyclotetradecin-2,5,11,13 (3H,6H,12H) -tetrone (I-12),compound of formula I where R¹ is[2-[3-(3-pyridinyl)-lH-1,2,4-triazol-1-yl]ethyl]thio, R² is fluoro, R³is methyl and Z is oxygen.

[0172] A] 3-(3-Pyridinyl)-1,2,4-triazole was prepared according to Linet al. J. Org. Chem. 1979,44,4160.

[0173] B ]-(2-Hydroxyethyl)-3-(3-pyridinyl)-1H-1 ,2,4-triazole

[0174] 3-(3-Pyridinyl)-1,2,4-triazole (1.6 g, 10.9 mmol) was suspendedin DMF (50 ml) and 0.964 g (10.9 mmol) ethylene carbonate was added.After addition of a catalytic amount of NaOH (8 mg), the mixture wasstirred at 160° C. for 2 hours. DMF was removed in vactuo and theresidue was crystallized from EtOH to give the desired product as asolid. MS (EI): 190.1 (M⁺). ¹H-NMR (DMSO-d6): 3.80 (q, 2H), 4.29 (t,2H), 5.01 (t, 1H), 7.50 (m, 1H), 8.31 (m, 1H), 8.59 (s, 1H), 8.62 (m,1H), 9.17 (d, 1H).

[0175] C]1-(2-Chloroethyl)-3-(3-pyridinyl)-1H- 1,2,4-triazole

[0176] 122 g (6.4 mmol) 1-(2-hydroxyethyl)-1H-1,2,4-triazole weresuspended in 15 ml thionyl chloride and heated at 70° C. for 45 minutes.Excess thionyl chloride was removed in vacuo and the residue wasdissolved in water (100 ml). The aqueous solution was basified withNaHCO₃ solution (10%) and the resulting slurry was stirred for 15minutes. The product was isolated by filtration, washed with water anddried to give the desired product as a brownish solid. MS (EI): 208.1(M+). ¹H-NMR (DMSO-d6): 3.97 (t, 2H), 4.54 (t, 2H), 7.38 (m, 1H), 8.21(s, 1H), 8.36 (m, 1H), 8.65 (m, 1H), 9.34 (d, 1H).

[0177] D]Ethanethioic acid,S-[[3-(3-pyridinyl)-1H-1,2,4-triazole-1-yl]ethyl]ester:

[0178] The title compound was obtained from1-(2-chloroethyl)-3-(3-pyridinyl)-1H-1,2,4-triazole following theprocedure described in example 10 step C. MS (EI): 248.1 (M⁺). ¹H-NMR(DMSO-d6): 2.34 (s, 3H), 3.36 (t, 2H), 4.44 (t, 2H), 7.51 (m, 1H), 8.31(m, 1H), 8.63 (m, 1H), 8.67 (s, 1H), 9.16 (d, 1H).

[0179] E]2- [3-(3-Pyridinyl)- 1H- 1,2,4-triazole-1-yl]ethanethiol:

[0180] The title compound was obtained from ethanethioic acid,S-[[3-(3-pyridinyl)-1H-1,2,4-triazole-1-yl]ethyl]ester following theprocedure described in example 10 step D. MS (EI): 206.1 (M⁺). ¹H-NMR(DMSO-d6): 2.50 (broad t, 1H), 2.98 (broad q, 2H), 4.41 (t, 2H), 7.51(m, 1H), 8.31 (m, 1H), 8.62 (m, 1H), 8.67 (s, 1H), 9.17 (s, 1H). F](10E)-3-de[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranosyl)oxy1-10,11-didehydro-11-deoxy-6-O-methyl-3-oxo-Erythromycin 2′-acetate (XXX-12)

[0181] To a solution of 0.4g (0.65mmol) of(1OE)-3-O-de(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranosyl)-10,11-didehydro-11-deoxy-6-O-methyl-erythromycin-2′acetate(XXIX, where R⁷ is methyl, Rp₁ is acetyl; J. Med. Chem. 1998, 41,1651-1659) in 5 ml dichloromethane were added dropwise at roomtemperature 2.76 g (0.98 mmol) of a 15% wt solution of Dess-Martinreagent in dichloromethane over a period of 10 minutes under argon. Thereaction mixture was stirred for 1h30 at room temperature. The resultingyellow solution was diluted with 5 ml diethyl ether and then poured intoa mixture of 45 g of a 10% aqueous solution of Na₂S₂0₃ and 4 g of asaturated NaHCO₃ solution and stirred for 1h. The organic layer wasseparated, the aqueous phase was extracted twice with 25 ml ofdiethylether. The combined organic phases were washed with 20 ml of 3%NaHCO₃, 20 ml water, 20 ml brine, dried over Na₂SO₄ and evaporated.Flash chromatography on silica gel with dichloromethane/methanol/ammonia90:10:1 gave 0.36g (90%) of XXX-12 as a colourless solid. MS (ISP):612.7 (MH⁺). ¹H-NMR (CDCl₃) diagnostic signals only: 0.93(t, 3H), 1.11(d, 3H), 1.15 (d, 3H), 1.22 (d, 3H), 1.31 (s, 3H), 1.35 (d, 3H), 1.48(s, 3H), 1,55-2,00 (m, 6H), 2.01 (s, 3H), 2.04 (s, 3H), 2.24 (s, 6H),2.65 (m, 1H), 2.86 (s, 3H), 3.00-3.20 (m, 2H), 3.54 (m, 1H), 3.72 (q,1H), 4.17 (d, 1H), 4.36 (d, 1H), 4.71 (m, 1H), 4.98 (dd, 1H), 6.59 (s,1H).

[0182]G](10E)-3-de[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranosyl)oxy]-10,11-didehydro-11-deoxy-2-fluoro-6-O-methyl-3-oxo-Erythromycin2′-acetate (XXXI-12)

[0183] This compound was obtained according to example 1F from XXX-12(0.5 g) and N-fluorobenzenesulfonimide (0.283 g). Yield: 0.24 g (46%).MS (ISP): 630.2 (MH⁺). ¹H-NMR (CDCl₃) diagnostic signals only: 0.95(t,3H), 1.16 (d, 3H), 1.17 (d, 3H), 1.22 (d, 3H), 1.28 (s, 3H), 1.49 (s,3H), 1,73 (d, 3H), 1.96 (s, 3H), 2.03 (s, 3H), 2.25 (s, 6H), 2.67 (s,3H), 3.46 (m, 2H), 3.96 (d, 1H), 4.72 (dd, 1H), 5.03 (dd, 1H), 6.59 (s,1H). H] (10E) -3-de[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranosyl)oxy]-10,11-didehydro-11 -deoxy-2-fluoro-6-O-methyl-3-oxo-erythromycin 2′-acetate12-(chloroacetate) (XXXII-12):

[0184] This compound was obtained according to example 1A from XXXI-12(0.15 g) and chloroacetic acid (67mg). Yield: 0.148 g (88%). MS (ISP):706.3 (MH⁺). ¹H-NMR (CDCl₃) diagnostic signals only: 0.97(t, 3H), 1.16(d, 3H), 1.17 (d, 3H), 1.22 (d, 3H), 1.28 (s, 3H), 1.49 (s, 3H), 1,71(s, 3H), 1.73 (d, 3H), 2.09 (s, 3H), 2.26 (s, 6H), 2.65 (s, 3H), 3.03(m, 2H), 3.46 (m, 2H), 4.01 (s, 2H), 4.39 (d, 1H), 4.76 (m, 1H), 4.97 (dbroad, 1H), 6.64 (s, 1H). I](10E)-3-de[(2,6-dideoxy-3-C-methyl-3-O-methyl-cc-L-ribo-hexopyranosyl)oxy]-10,11-didehydro-11-deoxy-2-fluoro-6-O-methyl-3-oxo-erythromycin2′-acetate 12- [[[2- [3-(3-pyridinyl)-1H-1 ,2,4-triazole-1-yl]ethyl]thio]acetate] (XXXIII-12)

[0185] To a solution of 35 mg (49.6 Rmol) XXXII-12 dissolved in 3 mlacetone were added 8.1 μl DBU and a catalytic amount of sodium iodide.10.7 mg (52.0 ,mol)2-[3-(3-pyridinyl)-1H-1,2,4-triazole-1-yl]ethanethiol were added in oneportion and the solution was stirred for 1 hour at room temperature. Thereaction mixture was diluted with CH₂Cl₂ washed with 5% aqueous NaHCO₃,dried over Na₂SO₄ and evaporated. The crude product was purified byflash chromatography on silica gel (CH₂Cl₂/MeOH/NH₃ 95:5:0.01) to give35 mg of the desired product as a foam. MS (ISP): 876.3 (MH⁺), 439.1((MH₂]⁺⁺). ¹H-NMR (CDCl₃), diagnostic signals only: 0.94 (t, 3H), 1.16(d, 3H), 1.24 (d, 3H), 2.08 (2, 3H), 2.25 (s, 6H), 3.15 (s, 3H),3.4-3.55 (m, 2H), 3.97 (d, 1H), 4.35-4.44 (m, 4H), 4.74 (dd, 1H), 5.46(dd, 1H), 6.62 (s, br, 1H), 7.37 (dd, 1H), 8.19 (s, 1H), 8.35 (m, 1H),8.64 (m, 1H), 9.32 (m, 1H).

[0186] K] (3R or S, 3aR, 4 R or S, 6R, 8R, 9R, lOR, 12S, 15R,15aS)-9-[[2-O-Acetyl-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-15-ethyl-12-fluorooctahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-3-[[2-[3-(3-pyridinyl)- 1H-1,2,4-triazole-1-yl]ethyl]thio]-2H-furo[2,3-c]oxacyclotetradecin-2,5,11,13 (3H,6H,12H) -tetrone (XXXIV-12)

[0187] To a solution of 11.4 mg (13.0 Mmol) XXXIII-12 in 2 ml dry DMFkept under argon at −5° C. were added 17.0 ,l of a solution of potassiumt-butoxide (1M in THF). The reaction mixture was stirred at −10 to −5°C. for 1 hour. The reaction was subsequently quenched with 2 ml of asaturated ammonium chloride solution and partitioned between ethylacetate and 3% aqueous NaHCO₃. The organic layer was washed twice with3% aqueous NaHCO₃ and once with half saturated brine, dried over Na₂SO₄and evaporated.

[0188] The crude product was purified by flash chromatography on silicagel (CH₂Cl₂/MeOH/NH₃ 98:2:0.01 -->97:3:0.01) to give 7.7 mg of thedesired product as a foam as a mixture of diastereomers. MS (ISP): 876.3(MH⁺), 439.0 ([MH₂]⁺⁺). ¹H-NMR (CDCl₃), diagnostic signals only (mainisomer): 0.90 (t, 3H), 2.07 (s, 3H), 2.26 (s, 6H), 2.37 (s, 1H), 2.50(s, 3H), 4.04 (d, 1H), 4.18 (s, 1H), 4.37 (d, 1H), 4.55-4.61 (m, 2H),4.75 (dd, 1H), 5.28 (dd, 1H), 7.36 (m, 1H), 8.33 (m, 1H), 8.56 (s, 1H),8.62 (m, 1H), 9.30 (m, 1H).

[0189] L] (3R or S, 3aR, 4R or S, 6R, 8R, 9R, IOR, 12S, 15R,15aS)-15-Ethyl-12-fluorooctahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-3-[[2-[3-(3-pyridinyl)-1H-1,2,4-triazole-1-yl]ethyl]thio]-9-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-2H-furo[2,3-c] oxacyclotetradecin-2,5,11,13 (3H,6H,12H)-tetrone (I-12)

[0190] The protected ketolide XXXIV-12 (13 mg, 14.8 mmol) was dissolvedin 3 ml methanol and stirred for 5 days at room temperature. The solventwas removed under reduced pressure and the crude product was purified byflash chromatography on silica gel (CH₂Cl₂/MeOH/NH₃ 94:6:0.01) to give6.0 mg of the desired product as a colorless solid as a singlediastereoisomer. ¹H-NMR (CDCl₃), diagnostic signals only: 0.90 (t, 3H),1.15 (d, 3H), 1.18 (d, 3H), 1.27 (d, 3H), 1.29 (d, 3H), 1.35 (s, 3H),1.75 (d, 3H),1.83-1.98 (m., 2H), 2.27 (s, 6H), 2.37 (s, 1H), 2.45, (m,1H), 2.51 (s, 3H), 2.60-2.68 (m, 1H), 3.07 (m, 1H), 3.13-3.21 (m, 2H),3.50- 3.64 (m, 4H), 4.06 (d, 1H), 4.18 (s, 1H), 4.30 (d, 1H), 4.55-4.63(m, 2H), 5.26 (dd, 1H), 7.35 (dd, 1H), 8.33 (m, 1H), 8.57 (s, 1H), 8.62(n, 11H), 9.30 (m, 1H).

EXAMPLE 13

[0191] Preparation of (3R or S, 3aR, 4R or S. 6R, 8R, 9R, lOR, 12S, 15R,15aS)-3-[[3-[6-Amino-9H-purine-9-yl]propyl]thio]-15-ethyl-12-fluorooctahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-3-9-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-2H-furo[2,3-c]oxacyclotetradecin-2,5,11,13 (3H,6H,12H)-tetrone (1-13), compoundof formula I where R¹ is [3-[6-Amino-9H-purine-9-yl]propyl]thio, R² isfluoro, R³ is methyl and Z is oxygen.

[0192] A] 3-[6-amino-9H-purine-yl]propanethiol

[0193] This side chain was prepared from6-amino-9-(3-chloropropyl)-9H-purine (J. Am. Chem. Soc. 1994, 116, 6089)following the procedures described in example 10, steps C and D.

[0194] The title compound I-13 was prepared starting from3-[6-amino-9H-purine-9-yl]-propanethiol 4and XXXII-12 according toexample 12 steps I-L with the only difference, that the cyclisation(step K) was performed at 0° C. MS (ISP) (MH⁺). ¹H-NMR (CDCl₃),diagnostic signals only: 0.93 (t, 3H), 1.12 (d, 3H), 1.18 (d, 3H), 1.23(d, 3H), 1.31 (d, 3H), 1.32 (s, 3H), 1.53 (s, 3H), 1.80 (d, 3H), 2.30(s, 6H), 2,69 (s, 3H), 4.08 (d, 1H), 4.14 (s, 1H), 4.32 (d, 1H),4.33-4.50 (m, 4H), 5.35 (dd, 1H), 5.48 (s, broad, 2H), 8.15 (s, 1H),8.36 (s, 1H).

EXAMPLE 14

[0195] Preparation of (3R or S) 3aR, 4R or S, 6R, 8R, 9R, lOR, 12S, 15R,15aS)-15-Ethyl-12-fluorooctahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-3-[[2-[[5-methyl-2,4-(1H,3H)-pyrimidinedione-1-yl]methoxy]ethyl]thio]-9-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-2H-furo[2,3-c] oxacyclotetradecin-2,5,11,13 (3H,6H,12H) -tetrone (1-14),compound of formula I where R¹ is[2-[[5-methyl-2,4-(1H,3H)-pyrimidinedione-1-yl]methoxy]ethyl]thio, R² isfluoro, R³ is methyl and Z is oxygen.

[0196] A]1- [(2-Hydroxyethoxy)methyl]-5-methyl-2,4(TH,3H)-pyrimidinedione

[0197] The title compound was prepared according to Ubasawa et al.,Chem. Pharm. Bull., 1995, 43, 142-143.

[0198] B]1- [(2-Chloroethoxy)methyl]-5-methyl-2,4(1H,3H)-pyrimidinedione

[0199] 150 mg (0.75 mmol)1-[(2-hydroxyethoxy)methyl]-5-methyl-2,4(1H,3H)-pyrimidinedione weredissolved in 10 ml pyridine and 1 g PS-triphenylphosphine resin (3mmol/g) and 147 μl carbontetrachloride were added. The reaction wasstirred at room temperature for 3 days. The reaction mixture was dilutedwith a mixture of ethyl acetate and methanol and centrifuged. Thesupernatant was decanted and the solvent was evaporated under reducedpressure. The residue, dissolved in ethyl acetate and a small amount ofmethanol, was purified by flash chromatography on silica gel (ethylacetate). The fractions containing the product were pooled and thevolume was reduced to about 3 ml. Upon addition of hexane the productcrystallized to give 97 mg of white crystals. MS (ISP):.217.1 (M-H⁴).¹H-NMR (DMSO-d₆): 1.77 (d, 3H), 3.69-3.77 (m, 4H), 5.10 (s, 2H), 7.59(d, 1H), 11,32 (s, br, 1H).

[0200] C] Ethanethioic acid, S- [2-[[-5-methyl-2,4(lH,3H)-pyrimidinedione-1-yl]methoxy]ethyl]ester

[0201] 92.0 mg (421 μmol)1-[(2-chloroethoxy)methyl]-5-methyl-2,4(1H,3H)-pyrimidinedione weresuspended in 6 ml acetone and 60.1 mg (526 μmol) potassium thioacetatewere added and the reaction mixture was heated to reflux for 6 hours.The suspension was concentrated in vactio and ethyl acetate was added.The organic layer was washed with water, dried over Na₂SO₄ andevaporated. The crude product was purified by flash chromatography onsilica gel (ethyl acetate/hexane 9:1) to give 73 mg ofthe desiredproduct. MS (ISP): 259.1 (MH⁺), 281.1 (MNa+). ¹H-NMR (DMSO-d₆): 1.76 (d,3H), 2.32 (s, 3H), 3.01 (t, 2H), 3.58 (t, 2H), 5.04 (s, 2H), 7.57 (d,1H), 11.32 (s, br, 1H).

[0202] D] 2- [[5-methyl-2,4-(1H,3H)-pyrimidinedione-1-yl]methoxy]ethanethiol

[0203] The title compound was prepared from 20 mg (77.4 lmol)ethanethioic acid,S-[2-[[-5-methyl-2,4(1H,3H)-pyrimidinedione-1-yl]methoxy]ethyl]esterfollowing the procedure described in example 10 step D. The crudeproduct was used immediately for the next reaction.

[0204] The title compound 1-14 was prepared starting from2-[[5-methyl-2,4-(1}H,3H)-pyrimidinedione-1-yl]methoxy]ethanethiol andXXXII-12 according to example 12 steps I-L with the only difference thatthe cyclisation (step K) was performed at 0° C. The product was isolatedas a mixture of two isomers. MS (ISP) 844.3 (MH⁺).

EXAMPLE 15

[0205] Preparation of (3R or S, 3aS, 4R or S, 6R, 8R, 9R, 10R, 12R, 15R,15aS)-15-Ethylhexadecahydro-4,6,8,10,12,15a-hexamethyl-2,5,11,13-tetraoxo-8-[[(2E) -3- (3-quinolyl)-2-propen- 1-yl]oxy]-9-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-2H-furo[2,3-c]oxacyclotetradecin-3-carbonitrile (I- 15), compound of formula Iwhere R¹ is cyano, R² is hydrogen, R³ is 3-(3-quinolyl)-2-propen-1-yland Z is oxygen.

[0206] A] 6-O-2-Propen-1-yl-erythromycin A 2′,4″-dibenzoate (111-15)

[0207] 6-O-2-Propen-1-yl-erythromycin A 2′,4″-dibenzoate was preparedfollowing procedures described in W00078773.

[0208] B] 6-O-2-Propen-1-yl-erythromycin A cyclic 11,12 carbonate2′,4″-dibenzoate (IV-15)

[0209] To a solution of 500 mg (509 μmol) 6-O-2-propen-1-yl-erythromycinA 2′,4″-dibenzoate (111-15) in 30 ml THF at −20° C. kept under argon 305μl (305 μmol) of a solution of sodium bis(trimethylsilyl)amide (1M inTHF) were added. After 10 minutes 165 mg (1.02 mmol)1,1′-carbonyldiimidazole were added and the temperature was allowed torise to −5° C. The reaction was stirred at -5° C to 0° C over night andadditional sodium bis(trimethylsilyl)amide (600 μl, 1M in THF) and1,1′-carbonyldiimidazole (83 mg, 0.51 mmol) were added. The reaction wasstirred at −5° C. to 0° C. until no starting material remained. Themixture was hydrolysed with water and ethyl acetate was added. Theorganic layer was washed with saturated NaHCO₃ and brine, dried overNa₂SO₄ and evaporated. The crude product (500 mg) was used for the nextreaction without further purification. MS (ISP): 1008.4 (MH⁺)

[0210] C] (10 E)-10,11-Didehydro-11-deoxy-6-O-2-propen-1-yl-erythromycin A2′,4Δ-dibenzoate (VI-15)

[0211] 500 mg (496 μmol) 6-O-2-Propen-1-yl-erythromycin A cyclic 11,12carbonate 2′,4″-dibenzoate were dissolved in 10 ml benzene and 185 μl(1.24 mmol) DBU were added. The reaction was heated to reflux for 12hours and diluted with ethyl acetate. The organic layer was washed withsaturated aqueous NaHCO₃, dried over Na₂SO₄ and evaporated. The crudeproduct was purified by flash chromatography on silica gel (ethylacetate/hexane 7:3) to give 200 mg of the desired product as a solid. MS(ISP): 964.4 (MH⁺), ¹H-NMR (CDCl₃), diagnostic signals only: 0.78 (d,3H), 0.84 (t, 3H), 0.98 (d, 3H), 1.68-1.91 (m, 6H), 1.97 (s, 3H), 2.32(s, 6H), 2.45 (d, 1H), 2.74-2.85 (m, 11H), 2.88-2.03 (mn, 1H), 3.27-3.38(m, 1H), 3.48 (s, 3H), 3.71 (d, 1H), 3.78-3.94 (m, 2H), 3.98-4.15 (m,2H), 4.45-4.58 (m, 1H), 4.82 (d, 1H), 4.87-5.00 (m, 3H), 5.02-5.14 (m,2H), 5.24 (dd, 1H), 6.49 (s, 1H), 7.36-7.65 (m ,6H), 7.95-8.09 (m, 4H).

[0212] D] (10E)-10,11-Didehydro-11-deoxy-6-O-2-propen- 1-yl-erythromycin A 2′,4″-dibenzoate 12-(chloroacetate) (VII-15)

[0213] The title compound was prepared starting with 166 mg of VI-15according to the procedure described in example 1, step A to give 128 mgof purified product. MS (ISP): 1040.5 (MH⁺).

[0214] E] (3R or S, 3aS, 4R or S, 6R, 8R, 9R, 10R, 12R, 15R, 15aS)-9-[[2-O-Benzoyl-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-11-[[2,6-dideoxy-3-C-methyl-3-O-methyl-4-O-(benzoyl-(α-L-ribo-hexopyranosyl]oxy]-15-ethylhexadecahydro-4,6,8,10,12,15a-hexamethyl-2,5,13-trioxo-8-[(2-propen-1-yl)oxy]-2H-furo [2,3-c] oxacyclotetradecin-3-carbonitrile (IX-15)

[0215] 200 mg (192 μmol) VII-15 were dissolved in 5 ml dichloromethaneat 0° C. and 96.5 mg (359 μl) tetrabutylammonium cyanide were added. Thetemperature was allowed to rise to room temperature. After 4 hours moretetrabutylammonium cyanide (25 mg, 93 μmol) was added and the reactionwas stirred over night at room temperature. The reaction mixture washeated to 40° C. during 4 hours. The solvent was evaporated and theresidue was purified by flash chromatography on silica gel (CH₂Cl₂/MeOH9:1) to give 170 mg of the desired product (mixture of diastereoisomers)as a solid. MS (ISP): 1031.4 (MH⁺).

[0216] F] (3R or S, 3aS, 4R or S, 6R, 8R, 9R, IOR, 12R, 15R,15aS)-9-[[2-O-Benzoyl-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy-15-ethylhexadecahydro-11-hydroxy-4,6,8,10,12,15a-hexamethyl-2,5,13-trioxo-8-[(2-propen-1-yl)oxy]-2H-furo[2,3-c] oxacyclotetradecin-3-carbonitrile (XI-15)

[0217] Compound IX-15 (170 mg, 165 μmol) was dissolved in a mixture of0.83 ml ethanol and 0.83 ml 2N hydrochloric acid and heated to 45° C.for 4 hours. The reaction was then stirred at room temperature during 16hours. 0.83 ml 3N sodium hydroxide were added and the reaction mixturewas extracted with ethyl aceteate. The organic layer was washed withsaturated aqueous NaHCO₃, dried over Na₂SO₄ and evaporated. The crudeproduct was purified by flash chromatography on silica gel (CH₂Cl₂/MeOH95:5) to give 100 mg of the desired product as a solid as a mixture ofdiastereomers. MS (ISP): 769.2 (MH⁺).

[0218] G] (3R or S, 3aS, 4R or S, 6R, 8R, 9R, IOR, 12R, 15R,15aS)-9-[[2-O-Benzoyl-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-15-ethylhexadecahydro-4,6,8,10,12,15a-hexamethyl-2,5,11,13-tetraoxo-8-[(2-propen-1-yl)oxy]-2H-furo[2,3-c] oxacyclotetradecin-3 -carbonitrile (XII-15)

[0219] 100 mg (130 μmol) XI-15, 167.0 mg (871 μmol) EDC*HCl and 166.3 μl(2.34 mmol) DMSO were dissolved in 8 ml dichloromethane at 0° C. and asolution of 168.3 mg (871 μmol) pyridinium trifluoroacetate in 2 mldichloromethane was added over a period of 10 minutes. The reactionmixture was stirred at room temperature during two hours. The solutionwas diluted with dichloromethane, washed with 3% aqueous NaHCO₃, driedover Na₂SO₄ and evaporated. The crude product was purified by flashchromatography on silica gel (ethyl acetate/hexane 7:3) to give 57 mg ofthe desired product as a solid as a mixture of diastereomers. MS (ISP):767.2 (MH⁺), ¹H-NMR (CDCl₃), diagnostic signals only: 0.88 (t, 3H), 0.99(d, 3H), 1.03 (d, 3H), 1.10 (d, 3H), 1.49 (s 3H), 2.27 (s, 6H),2.56-2.66 (m, 1H), 2.80-2.95 (m, 1H), 2.97-3.17 (m, 4H), 3.60-3.84 (m,5H), 4.39 (d, 1H), 4.61 (d, 1H), 4.69 (d, 1H), 4.98-5.13 (m, 4H), 5.39(dd, 1H), 5.60-5.76 (m, 1H), 7.39-7.48 (m, 2H), 7.52-7.60 (m, 1H),7.98-8.06 (m, 2H).

[0220] H] (3R or S, 3aS, 4R or S, 6R, 8R, 9R, IOR, 12R, 15R,15aS)-9-[[2-O-Benzoyl-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-15-ethylhexadecahydro-4,6,8,10,12,15a-hexamethyl-2,5,11,13-tetraoxo-8-[[(2E)-3-(3-quinolyl)-2-propen-1-yl]oxy]-2H-furo[2,3-c] oxacyclotetradecin-3-carbonitrile (XIII-15)

[0221] The product of step G (50 mg, 65 μmol), 2.9 mg (13 μmol)palladium(II)acetate, 6 mg (20 μmol) tri-o-tolylphosphine, 27.1 mg (130μmol) 3-bromoquinoline and 27.1 μl (196 μmol) triethylamine weredissolved in 1 ml acetonitrile in an autoclave and the solution wasdegassed and heated to 90° C. during 36 hours. The reaction mixture wasdiluted with dichloromethane washed with aqueous NaHCO₃, dried overNa₂SO₄ and evaporated. The crude product was purified by flashchromatography on silica gel (CH₂Cl₂/MeOH 98:2) to give 40 mg of thedesired product as a foam as a mixture of diastereoisomers. MS (ISP):894.3 (MH⁺), 448.0 ([MH₂]⁺⁺).

[0222] I] (3R or S, 3aS, 4R or S, 6R, 8R, 9R, lOR, 12R, 15R,15aS)-9-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-15-ethylhexadecahydro-4,6,8,10,12,15a-hexamethyl-2,5,11,13-tetraoxo-8-[[(2E)-3-(3-quinolyl)-2-propen- 1-yl]oxy] -2H-furo [2,3-c]oxacyclotetradecin-3-carbonitrile (1-15)

[0223] Compound XIII-15 (23 mg, 26 μmol) was dissolved in 3 ml methanoland heated to reflux for 5 hours. The solvent was removed and theresidue was purified by flash chromatography on silica gel (CH₂Cl₂/MeOH98:2) to give 11.7 mg of the desired product as a light yellow solid asa single diastereoisomer. MS (ISP): 790.5 (MH⁺), 396.0 ([MH₂]⁺⁺). ¹H-NMR(CDCl₃), diagnostic signals only: 0.93 (t, 3H), 1.07 (d, 3H), 1.09 (d,3H), 1.15 (d, 3H), 1.37 (d, 3H), 1.42 (d, 3H), 1.44 (s, 3H), 1.62 (s,3H), 2.24 (s, 6H), 2.39-2.48 (m, 1H), 2.64-2.74 (m, 1H), 3.12-3.30 (m,4H), 3.39-3.53 (m, 2H), 3.92-4.05 (m, 2H), 4.37 (d, 1H), 4.46 (d, 1H),4.75 (s, 1H), 5.45 (dd, 1H), 6.23-6.33 (m, 1H), 6.58 (d, 1H), 7.47-7.54(m, 1H), 7.61-7.68 (m, 1H), 7.81-7.86 (m, 1H), 8.03-8.09 (m, 1H), 8.15(d, 1H), 9.00 (d, 1H).

EXAMPLE 16

[0224] Preparation of (3R or S, 3aS, 4R or S, 6R, 8R, 9R, lOR, 12R, 15R,15aS)-15-Ethylhexadecahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-2,5,11,13-tetraoxo-9-[[3,4,6-trideoxy -3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-2H-furo[2,3-c] oxacyclotetradecin-3-carboxylic acid phenylmethyl ester (I-16),compound of formula I where R¹ is (phenylmethoxy)carbonyl, R² ishydrogen, R³ is methyl and Z is oxygen

[0225] A] (10E)- 10,11-Didehydro-11-deoxy-6-O-methyl-erythromycin2′-acetate 4″-(phenylmethyl carbonate) 12-[[(phenylmethoxy)carbonyl]acetate] (VIII- 16)

[0226] To a solution of 200 mg (221 μmol)(10E)-10,11-didehydro-11-deoxy-6-O-methyl-erythromycin 2′-acetate4″-(phenylmethyl carbonate) and 8.09 mg (66.2 μmol) DMAP in 10 mldichloromethane kept under argon were added a solution of 343 mg (˜50%purity; 883 μmol) monobenzyl malonate in 4 ml dichloromethane and asolution of 182 mg (883 μmol) DCC in 4 ml dichloromethane simultaneouslyover two days at room temperature. Following the addition, the reactionmixture was stirred at room temperature for further 12 hours. Thesolvent was partly evaporated under reduced pressure and the remainingsuspension was filtrated. The filtrate was diluted with dichloromethane,washed with 3% aqueous NaHCO₃, dried over Na₂SO₄ and evaporated. Thecrude product was purified twice by flash chromatography on silica gel(CH₂Cl₂/MeOH/NH₃ 97:3:0.01 -->96:4:0.01) to give 190 mg of the desiredproduct as a light yellow foam. MS (ISP): 1082.4 (MH⁺). ¹H-NMR (CDCl₃),diagnostic signals only: 0.81 (t, 3H), 0.91 (d, 3H), 1.82 (s, 3H), 2.00(s, 3H), 2.23 (s, 6H), 2.40 (d, 1H), 3.14 (s, 3H), 3.32 (s3H), 3.36 (s,2H), 4.68 (dd, 1H), 5.68 (dd, 1H), 6.59 (s, 1H), 7.25-7.41 (m, 10H).

[0227] B] (3R or S, 3aS, 4R or S, 6R, 8R, 9R, 1OS, 11S, 12R, 15R,15aS)-9-[[2-O-Acetyl-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-11[[2,6-dideoxy-3-C-methyl-3-O-methyl-4-O-[(phenylmethoxy)carbonyl]-α-L-ribo-hexopyranosyl]oxy]-15-ethylhexadecahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-2,5,13-trioxo-2H-furo[2,3-c] oxacyclotetradecin-3-carboxylic acid phenylmethyl ester; mixtureof diastereoisomers (IX-16)

[0228] To a solution of 56 mg (51.7 μmol) VIII-16 in 3 ml dry DMF keptunder argon at 0° C. were added 65.μl of a solution of potassiumt-butoxide (1M in THF). The reaction mixture was stirred at 0° C. for 1hour. The reaction was subsequently quenched with 2 ml of a saturatedNH₄Cl solution and partitioned between diethylether and 3% aqueousNaHCO₃. The organic layer was washed three times with 3% aqueous NaHCO₃,dried over Na₂SO₄ and evaporated. The crude product was submitted to arough purification by flash chromatography on silica gel(CH₂Cl₂/MeOH/NH₃ 97:3:0.01-->96:4:0.01) and directly used for the nextreaction. MS (ISP): 1082.4 (MH⁺).

[0229] C] (3R or S, 3aS, 4R or S, 6R, 8R, 9R, lOS, 11S, 12R, 15R,15aS)-9-[[2-O-Acetyl-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-15-ethylhexadecahydro-11-hydroxy-8-methoxy-4,6,8,10,12,15a-hexamethyl-2,5,13-trioxo-2H-furo[2,3-c] oxacyclotetradecin-3-carboxylic acid phenylmethyl ester; mixtureof diastereoisomers (XI-16)

[0230] The product of example 16 step B was dissolved in 4 ml methanolcontaining 3% HCl. The reaction mixture was stirred at room temperatureduring 3.5 hours and subsequently the solvent was evaporated. Theresidue was dissolved in dichloromethane, washed with 3% aqueous NaHCO₃,dried over Na₂SO₄ and evaporated. The crude product was purified byflash chromatography on silica gel (CH₂CI₂/MeOH/NH₃ 94:6:0.01-->93:7:0.01) to give 15 mg of the desired product (mixture ofdiastereoisomers) as a foam. MS (ISP): 790.2 (MH⁺).

[0231] D] (3R or S, 3aS, 4R or S, 6R, 8R, 9R, 10R, 12R, 15R,15aS)-9-[[2-O-Acetyl-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-15-ethylhexadecahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-2,5,11,13-tetraoxo-2H-furo[2,3-c] oxacyclotetradecin-3-carboxylic acid phenylmethyl ester; mixtureof diastereoisomers (XII-16)

[0232] 15 mg (19.0 1μmol) XI-16, 24.4 mg (127.2 lmol) EDC*HCI and 24.3μl (341.8 μmol) DMSO were dissolved in 1.5 ml dichloromethane and asolution of 24.6 mg (127.2 μmol) pyridinium trifluoroacetate in 0.5 mldichloromethane was added over a period of 10 minutes. The reactionmixture was stirred at room temperature during two hours. The solutionwas diluted with dichloromethane, washed with 3% aqueous NaHCO₃, driedover Na₂SO₄ and evaporated. The crude product was purified by flashchromatography on silica gel (CH₂Cl₂/MeOH/NH₃ 96:4:0.01 -->94:6:0.01) togive 12 mg of the desired product (mixture of diastereoisomers) as afoam. MS (ISP): 788.3 (MH⁺).

[0233] E] (3R or S, 3aS, 4R or S, 6R, 8R, 9R, IOR, 12R, 15R,15aS)-15-Ethylhexadecahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-2,5,11,13-tetraoxo-9-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-2H-furo[2,3-c] oxacyclotetradecin-3-carboxylic acid phenylmethyl ester (1-16)

[0234] The product of step D (XII-16; 13 mg, 14.8 mmol) was dissolved in4 ml methanol and stirred for 3 days at room temperature. The solventwas removed under reduced pressure and the crude product was purified byflash chromatography on silica gel (CH₂Cl₂/MeOH/NH₃ 95:5:0.01) to give2.5 mg of the desired product as a colorless solid as a singlediastereoisomer. ¹H-NMR (CDCl₃), diagnostic signals only: 0.79 (t, 3H),2.28 (s, 6H), 2.52 (s, 3H), 3.03-3.22 (m, 4H), 3.48-3.60 (m, 2H), 3.82(q, 1H), 4.19 (d, 1H), 4.31 (d, IH), 4.37 (d, 1H), 5.23 (s, 2H), 5.25(dd, 1H), 7.27-7.44 (m, 5H).

EXAMPLE 17

[0235] Preparation of 1-17, compound of formula I, where R¹ is[2-[4-(dimethylamino) phenyl]-2-oxoethyl]thio, R² is hydrogen, R³ ismethyl and Z is oxygen.

[0236] The title compound was prepared according to example 4 startingfrom XV-3 and α-bromo-4-diethylaminoacetophenone. MS (ISP): 833.3 (MH⁺).^(1H-NMR) (CDCl₃) diagnostic signals only: 0.89 (t, 3H), 1.14 (d, 3H),1.18 (d, 3H), 1.22 (t, 6H), 1.25 (s, 3H), 1.31 (d, 3H), 1.37 (d, 3H),1.51 (s, 3H), 1,55-1,80 (m, 3H), 1.95 (m, 1H), 2.31 (s, 6H), 2.62 (s,1H), 2.64(s, 3H), 3.02 (q, 1H), 3.05-3.15 (m, 1H), 3.22 (m, 1H), 3.42(q, 4H), 3.56 (m, 1H), 3.82 (q, 1H), 4.26 (d, 1H), 4.22 (d, 1H), 4.28(d, 1H), 4.40 (s, 1H), 5.50 (dd, 1H), 6.61 (d, 2H), 7.78 (d, 2H).

EXAMPLE 18

[0237] Preparation of I-18 compound of formula I, where R¹ is[2-(1H-2,3-dihydroindol-1-yl)-2-oxoethyl]thio, R² is hydrogen, R³ ismethyl and Z is oxygen.

[0238] The title compound was prepared according to example 4 startingfrom XV-3 and 1-(bromoacetyl)-2,3-dihydro-1H-Indole. MS (ISP): 803.3(MH⁺). ¹H-NMR (CDCl₃) diagnostic signals only: 0.90 (t, 3H), 1.12 (d,3H), 1.24 (d, 3H), 1.28 (s, 3H), 1.31 (d, 3H), 1.36 (d, 3H), 1.52 (s,3H), 1,55-1,80 (m, 4H), 1.95 (m, 1H), 2.28 (s, 6H), 2.45-2.60 (m, 3H),2.64 (s, 1H), 2.75 (s, 3H), 3.00-3.25 (m, 5H), 3.55 (m, 1H), 3.82 (q,1H), 3.93 (q, 2H), 4.12-4.20 (mn, 2H), 4.24 (d, 1H), 4.31 (d, 1H), 4.46(s, 1H), 5.50 (dd, 1H), 6.99 (t, 1H), 7.17 (t, 2H), 8.22 (d, 1H).

EXAMPLE 19

[0239] Preparation of (3R or S. 3aR, 4R or S, 6R, 8R, 9R, 10R, 12R, 15R,15aS)-15-Ethyloctahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-3- [[2-[(3-pyridinylcarbonyl)amino]ethyl]thio]-9-[[-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-2H-furo[2,3-c] oxacyclotetradecin-2,5,11,13 (3H,6H,12H)-tetrone (1-19) compoundof formula I, where R¹ is [2-[(3-pyridinylcarbonyl)amino]ethyl]thio, R²is hydrogen, R³ is methyl and Z is oxygen.

[0240] A] (10E)-10,11-didehydro-11-deoxy-6-0-methyl-erythromycin (V,scheme 1)

[0241] 35.4 g (47.3 mmol) clarithromycin, 35.4 g (402.4 mmol) ethylenecarbonate and 32.7 g (236.7 mmol) potassium carbonate dissolved in 200ml dry DMF were heated to 110° C. until no starting material remained(˜10 h). The mixture was then cooled to 50° C. and the solvent wasevaporated in vacuo. The residue was taken up in 1000 ml diethylether.The organic layer was washed twice with 400 ml aqueous NaHCO₃ 3%, driedover Na₂SO₄ and concentrated under reduced pressure to a small volumefrom which the desired product precipitated. The filtrate was purifiedby flash chromatography on silica gel (CH₂Cl₂:MeOH:NH₃ 96:4:0.01). 25.2g (73%) ofthe desired product V were obtained. MS (ISP): 730.4 (MH⁺).¹H-NMR (CDCl₃), diagnostic signals only: 0.90 (t, 3H), 1.10 (d, 3H),1.16 (d, 3H), 1.21 (d, 2H), 1.24 (s, 3H), 1.24 (d, 3H), 1.29 (d, 3H),1.40 (d, 3H), 1.41 (s, 3H), 1.55 (s, 3H), 2.01 (s, 3H), 2.27 (s, 6H),2.34-2.46 (m, 2H), 2.83-2.93 (m, 1H), 3.01 (dd, 1H), 3.19 (dd, 1H), 3.23(s, 3H), 3.31 (s, 3H), 3.38 (s, 3H), 3.42-3.51 (m, 1H), 3.67 (d, 1H),3.96-4.07 (m, 2H), 4.36 (d, 1H), 4.85 (d, 1H), 5.01 (dd, 1H), 6.63 (s,1H).

[0242] B] (10E)-10,11-didehydro-11-deoxy-6-O-methyl-erythromycin2′,4″-dibenzoate (VI-19), (scheme 1, formula VI)

[0243] To a solution of 16.9 g (23.2 mmol)(10E)-10,11-didehydro-11-deoxy-6-O-methyl-erythromycin (V) in 150 ml dryTHF kept under argon were added 2.83 g (23.2 mmol) DMAP, 12.9 ml (92.7mmol) triethylamine and 20.97 g (92.7 mmol) benzoic anhydride. Thereaction was stirred at 35° C. for two days. Most of the solvent wasevaporated and the residue was dissolved in 600 ml ethyl acetate. Theorganic layer was washed twice with 200 ml aqueous NaHCO₃5% and with 200ml brine, dried over Na₂SO₄ and concentrated in vacuo. The crude productwas purified by crystallisation from a small amount of ethylacetate/hexane and the mother liquors were subsequently purified byflash chromatography on silica gel (CH₂Cl₂:MeOH:NH₃ 97:3:0.01→95:5:0.01)to give 15.4 g (71%) of the desired product VI-19. MS (ISP): 938.4(MH⁺).

[0244] C] (10E)-10,11-didehydro-11-deoxy-6-O-methyl-erythromycin2′,4″-dibenzoate 12-(chloroacetate) (VII-19), (scheme 2, formula VII)

[0245] This compound was prepared from 8.6 g (9.17 mmol) of VI-19according to the procedure described in example 1 step A. The crudeproduct was purified by flash chromatography on silica gel(CH₂Cl₂:MeOH:NH₃98:2:0.01) to give 7.07 g (76%) of VII-19 as a foam. MS(ISP): 1014.5 (MH⁺).

[0246] D] (10E)-10,11-didehydro-11-deoxy-6-O-methyl-erythromycin2′,4″-dibenzoate 12-[[[2-[[(1,1-dimethylethoxy)carbonyl]amino]ethyl]thio]acetate] (VIII- 19), (scheme2, formula VIII)

[0247] To a solution of 5.8 g (5.7 mmol) VII-19 in 100 ml acetone wereadded 0.938 ml (6.28 mmol) DBU and a catalytic amount of sodium iodide.1.115 g (6.29 mmol) 2(-tert-Butoxycarbonylamino)ethanethiol were addedin one portion and the resulting suspension was stirred at roomtemperature for 1.5 hours. Most of the solvent was evaporated underreduced pressure and 150 ml dichloromethane were added to the residue.The organic layer was washed twice with 70 ml aqueous NaHCO3, dried overNa2SO4 and evaporated. The crude product was purified by flashchromatography on silica gel (CH₂Cl₂:MeOH:NH₃98:2:0.01) to give 5.68 g(86%) of VIII-19 as a foam. MS (ISP): 1155.5 (MH⁺).

[0248] E] (3R or S, 3aR, 4R or S, 6R, 8R, 9R, lOS, 11S, 12R, 15R,15aS)-9-[[2-O-Benzoyl-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-11-[[4-O-benzoyl-2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranosyl]oxy]-15-ethyldecahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-3-[2-[[(1,1-dimethylethoxy)carbonyl]amino]-ethyl]thio]-2H-furo [2,3-c]oxacyclotetradecin-2,5,13 (3H,6H)-trione; mixture of diastereomers;(IX-19), (scheme 2, formula IX)

[0249] To an ice cold solution of 2.0 g (1.73 mmol) VIII-19 in 20 ml dryDMF kept under argon were added 2.16 ml of a solution of KO^(t)Bu (1M inTHF). The reaction was stirred at 0° C. for 2 hours and then partitionedbetween 150 ml diethylether and 80 ml aqueous KH₂PO₄ (0.5 M). Theorganic layer was washed twice with 80 ml aqueous NaHCO₃3% and once with80 ml brine, dried over Na₂SO₄ and evaporated under reduced pressure.The crude product (1.91 g) was used for the next step without furtherpurification. MS (ISP): 1155.6 (MH⁺).

[0250] F] (3R or S, 3aR, 4R or S, 6R, 8R, 9R, lOS, 11S, 12R, 15R,15aS)-9-[[2-O-Benzoyl-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-15-ethyldecahydro-11-hydroxy-8-methoxy-4,6,8,10,12,15a-hexamethyl-3-[[2-[[(1,1-dimethylethoxy)carbonyl]-amino]ethyl]thio]-2H-furo[2,3-c] oxacyclotetradecin-2,5,13 (3H,6H)-trione; mixture ofdiastereomers; (XI-19), (scheme 2, formula XI). 1.90 g (1.64 mmol) ofIX-19 were dissolved in 100 ml methanol containing 3% HCN. The solutionwas kept at room temperature for 24 hours evaporated and dried underhigh vacuum. The crude hydrochloride salt was suspended in 20.0 ml THFand 12.0 ml N-ethyldiisopropylamine and 1.08 g (4.92 mmol)di-tert-butyl-dicarbonate were added. The reaction was stirred underargon at room temperature during two hours. Now 70 ml dichloromethanewere added and the organic layer was washed with 50 ml of saturatedaqueous NaHCO₃, 50 ml brine, dried over Na₂SO₄ and evaporated. The crudeproduct was purified by flash chromatography on silica gel(CH₂Cl₂:MeOH:NH₃98:2:0.01) to give 1.06 g (72.2%) of XI-19 as a foam. MS(ISP): 893.2 (MH⁺).

[0251] G] (3R or S, 3aR, 4R or S, 6R, 8R, 9R, lOR, 12R, 15R,15aS)-9-[[2-O-Benzoyl-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-15-ethyldecahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-3- [[2- [[(1,1-dimethylethoxy)carbonyl]-amino]ethyl]thio]-2H-furo[2,3-c] oxacyclotetradecin-2,5,13 (3H,6H, 12H)-tetrone; mixture ofdiastereomers; (XLIII-19), (scheme 11, formula XLIII).

[0252] This compound was prepared from 1.06 g (1.19 mmol) of XI-19according to the procedure described in example 1 step E. The crudeproduct was purified by flash chromatography on silica gel(CH₂Cl₂:MeOH:NH₃98:2:0.01) to give 0.87 g (82%) of XLIII-19 as a foam.MS (ISP): 891.4 (MH⁺).

[0253] H] (3R or S, 3aR, 4R or S, 6R, 8R, 9R, IOR, 12R, 15R,15aS)-3-[(2-aminoethyl)thio]-9-[[2-O-Benzoyl-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-15-ethyloctahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-2H-furo[2,3-c] oxacyclo-tetradecin-2,5,11,13 (3H,6H,12H)-tetrone (XLV-19)(scheme 11, formula XLV)

[0254] To a solution of 150 mg (0.168 mmol) XII-19 in 5 mldichloromethane were added 1.0 ml trifluoroacetic acid. The reaction wasstirred for 1 hour at room temperature. The mixture was diluted with 25ml dichloromethane and the organic layer was washed once with 20 mlsaturated aqueous NaHCO3, dried over Na2SO4 and evaporated. The crudeproduct (112 mg) was used for the next step without furtherpurification. MS (ISP): 791.2 (MH⁺) 396.2 ([MH₂]⁺⁺).

[0255] I] (3R or S, 3aR, 4R or S, 6R, 8R, 9R, 10R, 12R, 15R,15aS)-9-[[2-O-Benzoyl-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-15-ethyloctahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-3-[[2-[(3-pyridinylcarbonyl)amino]ethyl]thio]-2H-furo [2,3-c]oxacyclotetradecin-2,5,11,13 (3H,6H,12H)-tetrone (XII-19) (scheme 11,formula XII)

[0256] To a solution of 112 mg (˜0.14 mmol) crude XLV-19 in 15 mldichloromethane kept under argon were added 58.2 μl (0.42 mmol)triethylamine and 27.4 mg (0.154 mmol) 3-pyridinecarbonyl chloride. Thereaction mixture was stirred at room temperature until no startingmaterial remained (˜ two hours). The organic layer was washed with 10 mlsaturated aqueous NaHCO₃, dried over Na₂SO₄ and evaporated. The crudeproduct was purified by flash chromatography on silica gel(CH₂CI₂:MeOH:NH₃98:2:0.01) to give 100 mg (90%) of XII-19 as a foam. MS(ISP): 896.2 (MH^(t)), 448.6 ([MH₂]⁺⁺).

[0257] K] (3R or S, 3aR, 4R or S, 6R, 8R, 9R, lOR, 12R, 15R,15aS)-15-Ethyloctahydro-8-methoxy4,6,8,10,12,15a-hexamethyl-3-[[2-[(3-pyridinylcarbonyl)amino] ethyl]thio] -9-[[-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-2H-furo[2,3-c] oxacyclo-tetradecin-2,5,11,13 (3H,6H,12H)-tetrone (1-19) (scheme11, formula Ik)

[0258] 100 mg (112 μmol) XII-19 were dissolved in 5 ml methanol andstirred for 3 days at room temperature under argon. The solvent wasremoved under reduced pressure. The crude product was purified by flashchromatography on silica gel (CH,₂C₂:MeOH:NH₃95:5:0.01) to give 44 mg(50%) of I-19 as a single diastereoisomer. MS (ISP): 792.2 (MH⁺). ¹H-NMR(CDCl₃), diagnostic signals only: 0.87 (t, 3H), 1.11 (d, 3H), 1.14 (d,3H), 1.23 (s, 3H), 1.26 (d, 3H), 1.31 (d, 3H), 1.34 (d, 3H), 1.64-1.80(m) 3H)) 1.87-1.99 (m) 1H), 2.27 (s, 6H), 2.41-2.50 (m, 1H), 2.55 (s,3H), 2.56 (d, 1H), 2.57-2.65 (m, 1H), 2.91-3.01 (m, 1H), 3.03-3.12 (m,2H), 3.17 (dd, 1H), 3.30-3.37 (m, 1H), 3.51-3.61 (m, 1H), 3.63-3.74 (m,11H), 3.84 (q 1H), 4.10-4.19 (m, 1H), 4.23 (d, 1H), 4.28-4.33 (m, 2H),5.31 (dd, 1H), 7.30-7.35 (m, 11H), 7.65-7.73 (s, br, 1H), 8.19-8.26 (m,1H), 8.66-8.72 (m, 1H), 9.14-9.18 (m, 1H).

EXAMPLE 20

[0259] Preparation of I-20, compound of formula I, where R¹ is[2-[(2,1,3-benzoxadiazol-5-ylcarbonyl)amino]ethyl]thio, R² is hydrogen,R³ is methyl and Z is oxygen.

[0260] The title compound was prepared following the procedure describedin example 19 steps I-K starting from XLV-19 and2,1,3-benzoxadiazole-5-carbonyl chloride. MS (ISP): (MH⁺). ¹H-NMR(CDCl₃), diagnostic signals only: 0.87 (t, 3H), 1.07 (s, 3H) 1,12 (d,3H), 1.14 (d, 3H), 1.25 (d, 3H), 1.29 (d, 3H), 1.34 (d, 3H), 1.51 (d,3H), 1.51 (s, 3H), 1.63-1.81 (m, 3H), 1.88-1.97 (m, 1H), 2.26 (s, 6H),2.39-2.48 (m, 1H), 2.51 (s, 3H), 2.54-2.64 (m, 1H), 2.89-3.11 (m, 3H),3.15 (dd, 1H), 3.33-3.57 m, 3H), 3.64-3.76 (m, 1H), 3.82 (q, 1H),4.13-4.22 (m, 2H), 4.24-4.30 (m, 2H), 5.29 (dd, 1H), 7.83-7.91 (m, 2H),7.94-7.99 (m, 1H), 8.50-8.52 (m, 1H).

EXAMPLE 21

[0261] Preparation of I-21, compound of formula I, where R¹ is [2-[[[5-(2-pyridinyl)thien-2-yl]sulfonyl]amino]ethyl]thio, R² is hydrogen,R³ is methyl and Z is oxygen.

[0262] The title compound was prepared following the proceduresdescribed in example 19 steps I-K starting from XLV-19 and5-(2-pyridinyl)-2-thiophensulfonyl chloride. MS (ISP): (MH⁺). ¹H-NMR(CDCl₃), diagnostic signals only: 0.86 (t, 3H), 1.05 (d, 3H), 1.10 (d,3H), 1.21 (d, 3H), 1.25(d, 3H), 1.31 (d, 3H), 1.34 (s, 3H), 1.37 (d,3H), 1.47 (s, 3H), 2.27 (s, 6H), 2.41-2.51 (m, 1H), 2.55-2.64 (m, 11H),2.76 (s, 3H), 2.78-2.87 (m, 1H), 2.98-3.25 (m, 4H), 3.45-3.61 (m, 4H),3.83 (q, 1H), 4.15 (s, 1H), 4.26 (d, 1H), 4.32 (d, 1H), 5.21 (dd, 1H),6.00-6.06 (m, br, 1H), 7.46-7.49 (m, 11H), 7.59-7.62 (m, 1H), 7.64-7.68(m, 1H), 7.70-7.75 (m, 1H), 8.55-8.59 (m, 1H).

EXAMPLE 22

[0263] Preparation of I-22, compound of formula I, where R¹ is[2-[[(2,1,3-benzoxadiazol-4-yl)sulfonyl]amino]ethyl]thio, R² ishydrogen, R³ is methyl and Z is oxygen.

[0264] The title compound was prepared following the proceduresdescribed in example 19 steps I-K starting from XLV-19 and2,1,3-benzoxadiazole-5-sulfonyl chloride. MS (ISP): 867.3 (MH⁺).^(1H-NMR) (CDCl₃), diagnostic signals only: 0.87 (t, 3H), 1.02 (d, 3H),1.09 (d, 3H), 1.26 (d, 3H), 1.31 (d, 3H), 1.34 (s, 3H), 1.37 (d, 3H),1.47 (s, 3H), 1.84-1.94 (m, 1H), 2.27 (s, 6H), 2.75 (s, 3H), 2.79-2.89(m, 1H), 2.95-3.22 (m, 4H); 3.53-3.63 (m, 3H), 3.83 (q, 1H), 4.14 (s,1H), 4.27 (d, 1H), 4.33 (d, 1H), 5.20 (dd, 1H), 6.13 (s, br, 1H),7.49-7.57 (m, 1H), 8.03-8.10 (m, 2H).

EXAMPLE 23

[0265] Preparation of I-23 compound of formula I, where R¹ is[3-(4-cyanophenyl)prop-2-ynyl]thio, R² is hydrogen, R³ is methyl and Zis oxygen.

[0266] A] (3R or S, 3aR, 4R or S, 6R, 8R, 9R, 10S, 11S, 12R, 15R,15aS)-9-[[2-O-Acetyl-3,4,6-tri-deoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-15-ethyldecahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-3-[propyn-2-yl]thio-2H-furo [2,3-c] oxacyclotetradecin-2,5,11,13(3H,6H,12H)-tetrone (XVII-23, X =CH₂C≡C, Q =H)

[0267] Compound XVII-23 was obtained according to example 4 startingfrom XV-3 and propargylbromide, but without deprotection with methanol.MS (ISP): 724.4 (MH⁺).

[0268] B] (3R or S, 3aR, 4R or S, 6R, 8R, 9R, 10S, 11S, 12R, 15R,15aS)-9-[[2-O-Acetyl-3,4,6-tri-deoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-3-[(4-cyanophenyl)prop-2-ynyl-]thio-15-ethyldecahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-2H-furo [2,3-c]oxacyclotetradecin-2,5,11,13 (3H,6H,12H)-tetrone (XVIII-23)

[0269] A solution of 50 mg (69 pmol) XVII-23, in 1.5 ml acetonitrile and0.04 ml triethylamine was treated with 1 mg copper (I) iodide, 3.0 mgbis(triphenylphosphine) palladium (II) dichloride and 16 mg4-iodobenzonitrile for 24 h at room temperature under argon. Thereaction mixture was diluted with 20 ml dichloromethane, washed with 20ml 5% aqueous NaHCO3, 20 ml brine and evaporated. 55 mg (96%) of crudeXVIII-23 were obtained and used directly for the next step. MS (ISP):825.2 (MH⁺).

[0270] Deprotection of XVIII-23 was performed as described in example 1Gto give product I-23 as a colourless solid as a single diasteomer. MS(ISP): 783.3 (MH⁺). ¹H-NMR (CDCl₃) diagnostic signals only: 0.87 (t,3H), 1.14 (d, 3H), 1.16 (d, 3H), 1.22 (s, 3H), 1.31 (d, 3H), 1.38 (d,3H), 1.52 (s, 3H), 1,55-1,80 (m, 4H), 1.95 (m, 1H), 2.58 (s broad, 6H),2.65 (s, 1H), 2.78 (s, 3H), 3.00-3.25 (m, 2H), 3.45 (m, 1H), 3.66 (d,1H), 3.84 (q, 1H), 4.03 (d, 1H), 4.12-4.20 (m, 2H), 4.26 (d, 1H), 4.39(d, 1H), 4.59 (s, 1H), 5.45 (dd, 1H), 7.09 (d, 2H), 7.13 (d, 2H).

EXAMPLE 24

[0271] Preparation of I-24 compound of formula I, where R¹ is[2-[(phenylmethyl) aminolsulfonyl]ethyl]thio, R² is hydrogen, R³ ismethyl and Z is oxygen.

[0272] The title compound was prepared according to example 4 startingfrom XV-3 and N-(phenylmethyl)-ethenesulfonamide. MS (ISP): 841.3 (MH⁺).¹H-NMR (CDCl₃) diagnostic signals only: 0.86(t, 3H), 1.12 (d, 3H), 1.16(d, 3H), 1.25 (s, 3H), 1.28 (d, 3H), 1.31 (d, 3H), 1.36 (d, 3H), 1.50(s, 3H), 1,60-1,80 (m, 3H), 1.92 (m, 1H), 2.26 (s, 6H), 2.58 (s, 1H),2.70 (s, 3H), 2.90-3.25 (m, 6H), 3.35-3.60 (m, 4H), 3.82 (q, 1H),4.20-4.35 (m, 4H), 5.38 (dd, 1H), 7.20-7.40 (m, 5H).

EXAMPLE 25

[0273] Preparation of I-25 compound of formula I, where R¹ is[2-(8-quinolinylamino)-2-oxoethyl]thio, R² is fluoro, R³ is methyl and Zis oxygen.

[0274] A] (3R or S, 3aR, 4R or S, 6R, 8R, 9R, TOR, 12S, 15R,15aS)-9-[[2-O-Acetyl-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosylloxy]-15-ethyl-12-fluoroctahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-3-[(3-nitro-2-pyridinyl)dithiol -2H-furo [2,3-c]oxacyclo-tetradecin-2,5,11,13 (3H,6H,12H)-tetrone; mixture ofdiastereomers (XV-25).

[0275] Compound XV-25 was prepared according to example 3, step A bytreating compound XIV-1 with 3-nitro-2-pyridinesulfenylchloride. MS(ISP): 858.1 (MH⁺). ¹H-NMR (CDCl₃) diagnostic signals only: 1.01 (t,3H), 1.03 (d, 3H), 1.16 (d, 3H), 1.34 (s, 3H), 1.38 (d, 3H), 1.54 (s,3H), 1,55-1,75 (m, 2H), 1.78 (d, 3H), 2.27 (s broad, 6H), 2.59 (s, 1H),2.77 (s, 3H), 3.05-3.15 (m, 2H), 3.52 (m, 2H), 4.38 (d, 1H), 4.78 (m,1H), 5.82 (dd, 0.6 H), 5.92 (dd, 0.4H), 7.33 (dd, 1H), 8.52 (d, 1H),8.85 (d, 1H).

[0276] The title compound was prepared according to example 4 startingfrom XV-25 and 2-bromo-N-8-quinolyl-acetamide. MS (ISP): 847.6 (MH⁺).¹H-NMR (CDCl₃) diagnostic signals only: 0.93(t, 3H), 1.12 (d, 3H), 1.14(d, 3H), 1.23 (s, 3H), 1.26 (d, 3H), 1.31 (d, 3H), 1.55 (s, 3H),1.60-1,80 (m, 3H), 1.78 (d, 3H), 1.94 (m, 1H), 2.28 (s, 6H), 2.50 (s,1H), 2.72 (s, 3H), 3.01 (q, 1H), 3.18 (m, 1H), 3.44-3.62 (m, 2H), 3.72(d, 1H), 4.08 (d, 1H), 4.30 (d, 1H), 4.38 (s, 1H), 5.46 (dd, 1H), 7.40(dd, 1H), 7.45-7.55 (m, 2H), 8.16 (dd, 1H), 8.75-8.85 (m, 2H), 10.56 (s.broad, 1H).

EXAMPLE 26

[0277] Preparation of compound of formula I-26, where R¹ is[2-(5-quinolinylamino)-2-oxoethyllthio, R² is hydrogen, R³ is methyl andZ is oxygen.

[0278] The title compound was prepared according to example 4 startingfrom XV-3 and 2-chloro-N-(quinolin-5-yl)acetamide. MS (ISP): 828.5(MH⁺). ¹H-NMR (CDCl₃) diagnostic signals only: 0.91 (t, 3H), 1.05 (2d,6H), 1.26 (s, 3H), 1.32 (d, 3H), 1.40 (d, 3H), 1.56(s, 3H), 1,50-1,80(m, 3H), 1.96 (m, 1H), 2.26 (s, 6H), 2.61 (s, 1H), 2.81 (s, 3H), 3.00-3.20 (m, 3H), 3.58 (m, 1H), 3.63 (d, 1H), 3.84 (q, 1H), 4.09 (d, 1H),4.12-4.36 (m, 2H), IH), 4.44 (s, 1H), 5.40 (dd, 1H), 7.40-7.50 (m, 1H),7.71 (m, 1H), 7.90-8.10 (m, 2H), 8.42 (m, 1H), 8.95 (m, 1H), 9.50 (s,broad, 1H).

EXAMPLE 27

[0279] Preparation of (3R or S, 3aR, 4R or S, 6R, 8R, 9R, IOR, 12R, 15R,15aS)- 15-Ethyloctahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-3-[[2-[(3-quinolinylcarbonyl)amino]ethyl]thio]-9-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-2H-furo[2,3-c] oxacyclotetradecin-2,5,11,13 (3H,6H,12H)-tetrone (1-27) compoundof formula I, where R¹ is [2-[(3-quinolinylcarbonyl)amino]ethyl]thio, R²is hydrogen, R³ is methyl and Z is oxygen.

[0280] A] (3R or S, 3aR, 4R or S, 6R, 8R, 9R, lOR, 12R, 15R,15aS)-9-[[2-O-Benzoyl-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-15-ethyloctahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-3- [[2-[(3-quinolinylcarbonyl)amino]ethyl]thio]-2H-furo [2,3-c]oxacyclotetradecin-2,5,11,13 (3H,6H,12H)-tetrone (XII-27) (scheme 11,formula XII)

[0281] To a solution of 21.9 mg (0.126 mmol) 3-quinolinecarboxylic acid,69.1 mg (0.133 mmol) benzotriazol-1-yloxytripyrrolidinophosphoniumhexafluorophosphate and 65 μl N-ethyldiisopropylamine in 5 mldichloromethane were added after 10 minutes 100 mg (0.126 mmol) crudeXLV-19. The reaction mixture was stirred under an atmosphere of argon atroom temperature until no starting material remained (˜6 hours). Theorganic layer was washed with 10 ml saturated aqueous NaHCO₃, dried overNa₂SO₄ and evaporated. The crude product was purified by flashchromatography on silica gel (CH₂Cl₂:MeOH:NH₃98:2:0.01) to give 97 mg(81%) of XII-27 as a foam.

[0282] B] (3R or S, 3aR, 4R or S, 6R, 8R, 9R, lOR, 12R, 15R,15aS)-15-Ethyloctahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-3- [[2-[(3-quinolinylcarbonyl)amino]ethyl]thio]-9-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-2H-furo[2,3-c] oxacyclo-tetradecin-2,5,11,13 (3H,6H, 12H) -tetrone (I-27)(scheme 11, formula Ik)

[0283] 97 mg (103 pmol) XII-27 were dissolved in 5 ml methanol andstirred for 3 days at room temperature under argon. The solvent wasremoved under reduced pressure. The crude product was purified by flashchromatography on silica gel (CH₂Cl₂:MeOH:NH₃98:2:0.01) to give 23 mg(27%) of I-27 as a single diastereoisomer. MS (ISP): 842.4 (MH⁺). ¹H-NMR(CDCl₃), diagnostic signals only: 0.86 (t, 3H), 1.03 (s, 3H), 1.09 (d,3H), 1.12 (d, 3H), 1.22 (d, 3H), 1.27 (d, 3H), 1.32 (d, 3H), 1.49 (s,3H), 2.32 (s, 6H), 2.40 (s, 3H), 2.45-2.61 (m, 3H), 2.98-3.10 (m, 2H),3.12-3.21 (m, 2H), 3.32-3.40 (m, 1H), 3.48-3.58 (m, 1H), 3.68-3.85 (m,3H), 4.12 (d, 1H), 4.13-4.22 (m, 1H), 4.26 (d, 1H), 4.31 (s, 1H), 5.31(dd, 1H), 7.55-7.61 (m, lH), 7.72-7.80 (m, 1H), 7.80-7.86 (m, br, 1H),7.89-7.93 (m, 1H), 8.09-8.14 (m, 1H), 8.72 (m, 1H), 9.42 (m, 1H).

EXAMPLE 28

[0284] Preparation of I-28, compound of formula I, where R¹ is [2-[[[5-(dimethylamino)- 1-naphthalenyl]sulfonyl]amino]ethyl]thio, R² ishydrogen, R³ is methyl and Z is oxygen.

[0285] The title compound was prepared following the proceduresdescribed in example 19 steps I-K starting from XLV-19 and5-(dimethylamino)-1-naphthalenylsulfonyl chloride. MS (ISP): 918.1(MH⁺). ¹H-NMR (CDCl₃), diagnostic signals only: 0.86 (t, 3H), 1.04 (d,3H), 1.12 (d, 3H), 1.26 (d, 3H), 1.31 (d, 3H), 1.33 (s, 3H), 1.37 (d,3H), 1.48 (s, 3H), 2.28 (s, 6H), 2.42-2.62 (m, 3H), 2.66-2.75 (m, 1H),2.75 (s, 3H), 2.88 (s, 6H), 2.98-2.12 (m, 3H), 3.19 (dd, 1H), 3.31-3.39(m, 1H), 3.82 (q, 1H), 4.29 (d, 1H), 4.27 (d, 1H), 4.33 (d, 1H), 5.21(dd, 1H), 6.03 (br, 1H), 7.16 (d, 1H), 7.47-7.55 (m, 2H), 8.27 (d, 1H),8.39 (d, 1H), 8.52 (d, 1H).

EXAMPLE 29

[0286] Preparation of I-29, compound of formula I, where R¹ is[2-[[(8-quinolinyl)sulfonyl]amino]ethyl]thio, R² is hydrogen, R³ ismethyl and Z is oxygen.

[0287] The title compound was prepared following the proceduresdescribed in example 19 steps I-K starting from XLV-19 and8-quinolinesulfonyl chloride. MS (ISP): 876.3 (MH⁺). ¹H-NMR (CDCl₃),diagnostic signals only: 0.85 (t, 3H), 1.00 (d, 3H), 1.09 (d, 3H), 1.26(d, 3H), 1.29 (s, 3H), 1.31 (d, 3H), 1.37 (d, 3H), 1.45 (s, 3H),1.62-1.78 (m, 3H), 1.79-1.90 (m, 1H), 2.26 (s, 6H), 2.41-2.57 (m, 3H),2.70 (s, 3H), 2.73-2.89 (m, 1H), 2.90-3.01 (m, 2H), 3.04-3.13 (m,lH),3.13-3.21 (m, 1H), 3.29-3.37 (m, 2H), 3.47 (s, br, 1H), 3.513.61 (m,1H), 3.83 (q, 1H), 4.10 (s, 1H), 4.26 (d, 1H), 4.33 (d, 1H), 5.27 (dd,1H), 6.71 (dd, br, 1H), 7.51-7.58 (m, 1H), 7.60-7.68 (m, 1H), 8.00-8.07(m, TH), 8.22-8.28 (m, 1H), 8.41-8.47 (m, 1H), 9.05-9.11 (m, 1H).

EXAMPLE 30

[0288] Preparation of 1-30, compound of formula I, where R¹ is[2-[[(1,3-benzodioxol-5-yl)methyl]amino]-2-oxoethyl]thio, R² ishydrogen, R³ is methyl and Z is oxygen.

[0289] The title compound was prepared following the procedure describedin example 4 starting from XV-3 andN-(1,3-benzodioxol-5-ylmethyl-2-chloro-acetamide. MS (ISP): 835.32(MH⁺).

EXAMPLE 31

[0290] Preparation of 1-31, compound of formula I, where R¹is[2-[(2-furanylmethyl)amino]-2-oxoethyl]thio, R² is hydrogen, R³ ismethyl and Z is oxygen.

[0291] The title compound was prepared following the procedure describedin example 4 starting from XV-3 and2-chloro-N-(2-furanylmethyl)-acetamide. MS (ISP): 781.3 (MH⁺).

EXAMPLE 32

[0292] Preparation of I-32, compound of formula I, where R¹ is[2-[(2-pyridinylmethyl)amino]-2-oxoethyl]thio, R² is hydrogen, R³ ismethyl and Z is oxygen.

[0293] The title compound was prepared following the procedure describedin example 4 starting from XV-3 and2-chloro-N-(2-pyridinylmethyl)-acetamide. MS (ISP): 882.36 (MH⁺).

EXAMPLE 33

[0294] Preparation of I-33, compound of formula I, where R¹ is[2-[(5-methyl-3-isoxazolyl)amino]-2-oxoethyl]thio, R² is hydrogen, R³ ismethyl and Z is oxygen.

[0295] The title compound was prepared following the procedure describedin example 4 starting from XV-3 and2-chloro-N-(5-methyl-3-isoxazolyl)-acetamide. MS (ISP): 782.3 (MH⁺).

EXAMPLE 34

[0296] Preparation of 1-34, compound of formula I, where R¹ is[2-[(2-benzothiazolylmethyl)amino]-2-oxoethyl]thio, R² is hydrogen, R³is methyl and Z is oxygen.

[0297] The title compound was prepared following the procedure describedin example 4 starting from XV-3 andN-(2-benzothiazolylmethyl)-2-chloro-acetamide. MS (ISP): 848.3 (MH⁺).

EXAMPLE 35

[0298] Preparation of I-35, compound of formula I, where R¹ is[2-[(1H-imidazol-2-ylmethyl)amino]-2-oxoethyl]thio, R² is hydrogen, R³is methyl and Z is oxygen.

[0299] The title compound was prepared following the procedure describedin example 4 starting from XV-3 and2-chloro-N-(1H-imidazol-2-ylmethyl)-acetamide. MS (ISP): 781.3 (MH⁺).

EXAMPLE 36

[0300] Preparation of compound of formula I-36, where R¹ is[3-(5-quinolinylamino)-3-oxopropylithio, R² is hydrogen, R³ is methyland Z is oxygen.

[0301] The title compound was prepared according to example 4 startingfrom XV-3 and N-5-quinolinyl-2-propenamide. MS (ISP): 842.2 (MH⁺).¹H-NMR (CDCl₃) diagnostic signals only: 0.84 (t, 3H), 1.10 (1d, 3H),1.19 (s, 3H), 1.21 (s, 3H), 1.26 (d, 3H), 1.31 (d, 3H), 1.51 (s, 3H),1.96 (m, 1H), 2.23 (s, 6H), 2.27 (s, 3H), 2.58 (s, 1H), 2.90- 3.25 (m,7H), 3.40-3.60 (m, 3H), 3.79 (q, 1H), 4.02 (d, 1H), 4.22 (d, 1H), 1H),4.35(s, 1H), 5.27 (dd, 1H), 7.42 (dd, 1H), 7.69 (t, 1H), 7.90 (d, 1H),8.05 (d, 1H), 8.53 (d, 1H), 8.90 (s broad, 1H).

EXAMPLE 37

[0302] Preparation of I-37 compound of formula I, where R¹ is[2-(2-quinolinylamino)-2-oxoethyl]thio, R² is hydrogen, R³ is methyl andZ is oxygen.

[0303] The title compound was prepared according to example 4 startingfrom XV-3 and 2-chloro-N-2-quinolinyl-acetamide. MS (ISP): 828.4 (MH⁺).¹H-NMR (CDCl₃) diagnostic signals only: 0.95 (t, 3H), 1.11 (d, 3H), 1.27(d, 3H), 1.35 (d, 3H), 1.41 (s, 3H), 1.43 (s, 3H), 1.53 (s, 3H),1,50-1,80 (m, 3Hj, 1.94 (m, 1H), 2.27 (s, 6H), 2.40-2.60 (m, 2H), 2.71(s, 1H), 2.92 (s, 3H), 3.00-3.25 (m, 4H), 3.50-3.60 (m, 2H), 3.62 (d,1H), 3.85 (q, 1H), 4.02 (d, 1H), 4.28 (d, 1H), 4.34 (d, 1H), 4.43 (s,1H), 5.43 (dd, 1H), 7.41 (t, 1H), 7.61 (t, 1H), 7.76 (d, 1H), 7.82 (d,1H), 8.16 (d, 1H), 8.45 (d, 1H), 9.41 (s broad, 1H).

EXAMPLE 38

[0304] Preparation of I-38 compound of formula I, where R¹ is[2-(6-quinolinylamino)-2-oxoethyl]thio, R² is hydrogen, R³ is methyl andZ is oxygen.

[0305] The title compound was prepared according to example 4 startingfrom XV-3 and 2-chloro-N-6-quinolinyl-acetamide. MS (ISP): 828.4 (MH⁺).¹H-NMR (CDCl₃) diagnostic signals only: 0.89 (t, 3H), 1.12 (d, 3H), 1.17(d, 3H), 1.31 (d, 3H), 1.35 (s, 3H), 1.52 (s, 3H), 1,50-1,80 (m),33H),1.96 (m, 1H), 2.26 (s, 6H), 2.40-2.70 (m, 2H), 2.62 (s, 1H), 2.83 (s,3H), 3.05-3.25 (m, 4H), 3.50-3.60 (m, 2H), 3.58 (d, 1H), 3.87 (q, 1H),4.14 (d, 1H), 4.15 (d, 1H), 4.29 (d, 1H), 4.30-4.40 (m, 2H), 5.33 (dd,1H), 7.38 (dd, 1H), 7.99 (dd, 1H), 8.05 (d, 1H), 8.13 (d, 1H), 8.61 (m,1H), 8.83 (m), H), 9.54 (s broad, 1H).

EXAMPLE 39

[0306] Preparation of I-39 compound of formula I, where R¹ is[2-(3-quinolinylamino)-2-oxoethyl]thio, R² is hydrogen, R³ is methyl andZ is oxygen.

[0307] The title compound was prepared according to example 4 startingfrom XV-3 and 2-chloro-N-3-quinolinyl-acetamide. MS (ISP): 828.4 (MH⁺).^(1H-NMR) (CDCl₃) diagnostic signals only: 0.92 (t, 3H), 1.12 (d, 3H),1.16 (d, 3H), 1.28 (d, 3H), 1.34 (d, 3H), 1.42 (s, 3H), 1.53 (s, 1H),1,50-1,80 (m, 3H), 1.95 (m, 1H), 2.26 (s, 6H), 2.40-2.50 (m, 1H), 2.58(s, 1H), 2.65-2.75 (m, 1H), 2.85 (s, 3H), 3.05-3.25 (m, 3H), 3.50-3.60(m, 1H), 3.54 (d, 1H), 3.86 (q, 1H), 4.26 (d, 1H), 4.30-4.45 (m, 3H),5.30 (dd, 1H), 7.52 (m, 1H), 7.62(m, 1H), 7.82 (d, 1H), 8.05 (d, 1H),9.01 (m, 1H), 9.18 (m, 1H), 9.69 (s broad, 1H).

EXAMPLE 40

[0308] Preparation of I-40 compound of formula I, where R¹ is[2-(5-isoquinolinylamino)-2-oxoethyl]thio, R² is hydrogen, R³ is methyland Z is oxygen.

[0309] The title compound was prepared according to example 4 startingfrom XV-3 and 2-chloro-N-5-isoquinolinyl-acetamide. MS (ISP): 828.4(MH⁺). ¹H-NMR (CDCl₃) diagnostic signals only: 0.91 (t, 3H), 1.10 (d,3H), 1.12 (d, 3H), 1.28 (d, 3H), 1.31 (s, 3H), 1.41 (s, 3H), 1.53 (s,1H), 1,50-1,80 (m, 3H), 1.94 (m, 1H), 2.26 (s, 6H), 2.40-2.50 (m, 2H),2.62 (s, 1H), 2.83 (s, 3H), 3.05-3.20 (m, 3H), 3.45-3.60 (m, 1H), 3.63(d, 1H), 3.87 (q, 1H), 4.20 (d, 1H), 4.28 (d, 1H), 4.31 (d, 1H), 4.46(s, 1H), 5.42 (dd, 1H), 7.63 (t, 1H), 7.82(d, 1H), 7.90 (d, 1H), 8.32(d, 1H), 8.55 (d, 1H), 9.26 (s, 1H), 9.54 (s broad, 1H).

EXAMPLE 41

[0310] Preparation of I-41 compound of formula I, where R¹ is[3-(6-quinolinylamino)-3-oxopropyl]thio, R² is hydrogen, R³ is methyland Z is oxygen.

[0311] The title compound was prepared according to example 4 startingfrom XV-3 and N-6-quinolinyl-2-propenamide. MS (ISP): 842.3 (MH⁺).¹H-NMR (CDC1₃) diagnostic signals only: 0.85 (t, 3H), 1.01 (s, 3H), 1.18(d, 3H), 1.21 (d, 3H), 1.31 (s, 3H), 1.51 (s, 3H), 1,50-1,80 (m, 3H),1.91 (m, 1H), 2.24 (s, 6H), 2.39 (s, 3H), 2.40-2.50 (m, 2H), 2.62 (s,1H), 2.90-3.20 (m, 6H), 3.40-3.55 (m, 3H), 3.82 (q, 1H), 4.12 (d, 1H),4.26 (d, 1H), 4.35 (s, 1H), 5.32 (dd, 1H), 7.33 (dd, 1H), 7.72(dd, 1H),8.00 (d, 1H), 8.11 (d, 1H), 8.51 (m, IH), 8.77 (s broad, IH), 9.54 (m,1H).

EXAMPLE 42

[0312] Preparation of I-42 compound of formula I, where R¹ is[3-(3-quinolinylamino)-3-oxopropyl]thio, R² is hydrogen, R³ is methyland Z is oxygen.

[0313] A] N-3-quinolinyl-2-propenamide

[0314] 0.39g (3.81 mmol) triethylamine were added to a suspension of 0.5g (3.47 mmol) 3-aminoquinoline in 5 ml acetone. 0.35 g (3.81 mmol)acrylic acid chloride were added dropwise to the suspension at 0° C. Theyellow suspension was stirred at 0° C. for 1 h. The reaction mixture wasdiluted with 25 ml 3% NaHCO₃ and extracted twice with 25 ml ethylacetate. The combined organic phases were washed with 25 ml water, 25 mlbrine, dried over MgSO4 and the solvent was removed under reducedpressure. The crystalline material was triturated with 10 mlethylacetate. 0.354 g (51.5%) of a beige product were isolated byfiltration and dried at room temperature in vacito. MS (ISP): 199.3(MH⁺). ¹H-NMR (CDCl₃): 5.85 (dd, 1H), 6.34 (dd, 1H), 6.55 (dd, 1H),7.56-7.70 (m, 2H), 7.90 (m, 2H), 8.79 (m, 1H), 8.95 (m, 1H).

[0315] B] The title compound was prepared according to example 4starting from XV-3 and N-3-quinolinyl-2-propenamide. MS (ISP): 842.3(MH⁺). ¹H-NM,R (CDCl₃) diagnostic signals only: 0.85 (t, 3H), 0.90 (s,3H), 1.14 (d, 3H), 1.21 (d, 3H), 1.25 (d, 3H), 1.29 (d, 3H), 1.31 (d,3H), 1.55 (s, 3H), 1,50-1,80 (m, 3H), 1.92 (m, 1H), 2.24 (s, 6H), 2.33(s, 3H), 2.62 (s, 1H), 2.85-3.20 (m, 6H), 3.40-3.55 (m, 3H), 3.81 (q,IH), 4.09 (d, IH), 4.23 (d, 1H), 4.38 (s, 1H), 5.32 (dd, 1H), 7.48 (dd,IH), 7.57(dd, 1H), 7.78 (d, 1H), 7.98 (d, 1H), 8.88 (m, 1H), 8.91 (sbroad, 1H).

EXAMPLE 43

[0316] Preparation of (3R or S, 3aR, 4R or S, 6R, 8R, 9R, 10R, 12R, 15R,15aS)-15-Ethyloctahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-3-[[2-[(3-pyridinylcarbonyl)amino]ethyl]sulfonyl]-9-[[-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]- 2H-furo[2,3-c] oxacyclotetradecin-2,5,11,13 (3H,6H,12H)-tetrone (1-43) compoundof formula I, where R¹ is [2-[(3-pyridinylcarbonyl)amino]ethyl]sulfonyl,R² is hydrogen, R³ is methyl and Z is oxygen.

[0317] A] (3R or S, 3aR, 4R or S, 6R, 8R, 9R; IOR, 12R, 15R,15aS)-9-[[2-O-Benzoyl-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-15-ethyldecahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-3-[[2-[[(1,1 -dimethylethoxy) carbonyl]amino]ethyl]sulfonyl]-2H-furo[2,3-c] oxacyclotetradecin-2,5,13 (3H,6H, 12H)-tetrone; mixture ofdiastereomers; (XLIV-43), (scheme 11, formula XLIV).

[0318] To a solution of 150 mg (0.168 mmol) XLIII-19 in 5 mldichloromethane at 0° C. were added 247 mg (2.94 mmol) sodiumbicarbonate and 363 mg (1.47 mmol) m-chloroperbenzoic acid. The mixturewas allowed to warm to room temperature and stirred for 4 days. 5 ml ofan aqueous sodium pyrosulfite solution were added and the mixture wasstirred vigorously for 1 hour. The pH of the solution was adjusted to pH9 with saturated aqueous sodium carbonate and extracted twice with 10 mldichloromethane. The combined organic layers were washed with 10 mlaqueous NaHCO₃ 3%, 10 ml brine, dried over Na₂SO₄ and evaporated to give148 mg of a light yellow solid. MS (ISP): 923.3 (MH⁺).

[0319] B] (3R or S, 3aR, 4R or S, 6R, 8R, 9R, lOR, 12R, 15R,15aS)-3-[(2-aminoethyl)sulfonyl]-9-[[2-O-Benzoyl-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-15-ethyloctahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-2H-furo[2,3-c] oxacyclo-tetradecin-2,5,11,13 (3H,6H, 12H)-tetrone (XLV-43)(scheme 11, formula XLV, p=2)

[0320] This compound was prepared following the procedure described inexample 19 step H starting from XLIV-43. MS (ISP): 823.2 (MH⁺) 412.5([MH₂]⁺⁺).

[0321] C] (3R or S, 3aR, 4R or S, 6R, 8R, 9R, lOR, 12R, 15R,15aS)-9-[[2-O-Benzoyl-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-15-ethyloctahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-3-[[2- [(3-pyridinylcarbonyl)amino]ethyl]sulfonyl]-2H-furo [2,3-c]oxacyclotetradecin-2,5,11,13 (3H,6H,12H)-tetrone (XII-43) (scheme 11,formula XII)

[0322] This compound was prepared following the procedure described inexample 19 step I starting from XLV-43 and 3-pyridinecarbonyl chloride.MS (ISP): 928.3 (MH⁺).

[0323] D] (3R or S, 3aR, 4R or S, 6R, 8R, 9R, lOR, 12R, 15R,15aS)-15-Ethyloctahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-3-[[2-[(3-pyridinylcarbonyl)amino]ethyl]sulfonyl]-9-[[-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-2H-furo[2,3-c] oxacyclotetradecin-2,5,11,13 (3H,6H, 12H)-tetrone (1-43) (scheme11, formula Ik).

[0324] This compound was prepared following the procedure described inexample 19 step K. MS (ISP): 824.5 (MH⁺). ¹H-NMR (CDCl₃), diagnosticsignals only: 0.87 (t, 3H), 0.92 (d, 3H), 1.08 (d, 3H), 2.30 (s, 6H),2.80 (s, 3H), 3.29 (s, 1H), 3.87 (q, 1H), 4.36 (d, 1H), 4.37 (d, 1H),4.93 (s, 1H), 5.62 (dd, 1H), 7.30-7.37 (m, 1H), 7.65 (dd, br, 1H),8.11-8.18 (m, 1H), 8.68-8.73 (m, 1H), 9.00-9.06 (m, 1H)

EXAMPLE 44

[0325] Preparation of I-44, compound of formula I, where R¹ is[2-[(2,1,3-benzoxadiazol-5-ylcarbonyl)amino]ethyllsulfonyl, R² ishydrogen, R³ is methyl and Z is oxygen.

[0326] The title compound was prepared following the procedure describedin example 43 steps B-D starting from XLV-43 and2,1,3-benzoxadiazole-5-carbonyl chloride. MS (ISP): 865.5 (MH⁺). ¹H-NMR(CDCl₃), diagnostic signals only: 0.88 (t, 3H), 0.99 (d, 3H), 1.07 (d,3H), 1.27 (d, 3H), 1.30 (s, 3H), 1.34 (d, 3H), 1.37 (d, 3H), 1.60 (s,3H), 2.27 (s, 6H), 2.81 (s, 3H), 3.87 (q, 1H), 4.35 (d, 1H), 4.37 (d,1H), 4.97 (s, 1H), 5.62 (dd, 1H), 7.80 (dd, br, 1H), 7.84-7.94 (m, 2H),8.36 (s, 1H).

EXAMPLE 45

[0327] Preparation of I-45, compound of formula I, where R¹ is [2-[2,4-dimethoxyphenyl]-2-oxoethyl]thio, R2 is hydrogen, R³ is methyl andZ is oxygen.

[0328] The title compound was prepared following the procedure describedin example 4 starting from XV-3 and2-bromo-1-(2,4-dimethoxyphenyl)-ethanone. MS (ISP): 822.38 (MH⁺).

EXAMPLE 46

[0329] Preparation of (3R or S, 3aR, 4R or S, 6R, 8R, 9R, 10R, 12R, 15R,15aS)-3-[[2-[(5-Cyanopyridin-2-yl)amino]ethyl]thio]-15-ethyloctahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-9-[[-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-2H-furo [2,3-c] oxacyclotetradecin-2,5,11,13 (3H,6H,12H)-tetrone (I-46)compound of formula I, where R¹ is[2-[(5-cyanopyridin-2-yl)amino]ethyl]thio, R² is hydrogen, R³ is methyland Z is oxygen.

[0330] A] (3R or S, 3aR, 4R or S, 6R, 8R, 9R, lOR, 12R, 15R,15aS)-9-[[2-O-Benzoyl-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-3-[[2-[(5-Cyanopyridin-2-yl)amino]ethyl]thio]-15-ethyloctahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl2H-furo [2,3-c] oxacyclotetradecin-2,5,11,13 (3H,6H,12H)-tetrone(XII-46).

[0331] To a solution of 130mg (˜0.16 mmol) crude XLV-19 and 75 II (0.54mmol) triethylamine in 20 ml acetonitrile were added 33.8 mg (0.25 mmol)6-chloro-3-pyridinecarbonitrile. The reaction mixture was heated toreflux during 36 hours. 50 ml ethyl acetate were added and the organiclayer was washed with 10 ml saturated aqueous NaHCO₃, dried over Na₂SO₄and evaporated. The crude product was purified by flash chromatographyon silica gel (CH₂Cl₂:MeOH:NH₃ 98:2:0.01) to give 81 mg (55%) of XII-46as a foam. ¹H-NMR (CDCl₃), diagnostic signals only: 0.83 (t, 3H), 2.26(s, 6H), 2.72 (s, 3H), 3.71 (q, 1H), 4.56 (d, 1H), 5.04 (dd, 1H), 5.29(dd, 1H), 6.20 (s, br, 1H), 6.50 (d, 1H), 7.39-7.61 (m, 4H), 7.99-8.07(m, 2H), 8.35 (d, 1H).

[0332] B] (3R or S, 3aR, 4R or S, 6R, 8R, 9R, lOR, 12R, 15R,15aS)-3-[[2-[(5-Cyanopyridin-2-yl)amino]ethyl]thio]-15-ethyloctahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-9-[[-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]- 2H-furo[2,3-c] oxacyclotetradecin-2,5,11,13 (3H,6H,12H)-tetrone (1-46).

[0333] The product of step A (23 mg, 0.027 mmol) was dissolved in 5 mlmethanol and stirred for 4 days at room temperature. The solvent wasremoved under reduced pressure and the product was purified by flashchromatography on silica gel (CH₂Cl₂:MeOH:NH₃ 98:2:0.01) to give 44 mg(62%) of 1-46 as a single diastereoisomer. MS (ISP): 789.5 (MH⁺). ¹H-NMR(CDCl₃), diagnostic signals only: 0.87 (t, 3H), 1.10 (d, 3H), 1.15 (d,3H), 1.26 (d, 3H), 1.32 (d, 3H), 1.33 (s, 3H), 1.36 (d, 3H), 1.50 (s,3H), 1.64-1.84 (m, 3H), 1.86-1.98 (m,l H), 2.26 (s, 6H), 2.41-2.51 (m,1H), 2.54-2.64 (m, 2H), 2.74 (s, 3H), 2.92-3.02 (m, 1H), 3.02-3.13 (m,2H), 3.18 (dd, 1H), 3.22-3.31 (m, 1H), 3.48 (s, br, 1H), 3.52-3.61 (m,2H), 3.47-3.91 (m, 3H), 4.24-4.30 (m, 2H), 4.33 (d, 1H), 5.31 (dd, 1H),6.22 (s, br, 1H), 6.51 (d, 1H), 7.50 (dd, 1H), 8.36 (d, 1H).

EXAMPLE 47

[0334] Preparation of I-47, compound of formula I, where R¹ is[2-[(6-quinolinylcarbonyl)amino]ethyl]thio, R² is hydrogen, R³ is methyland Z is oxygen.

[0335] The title compound was prepared following the proceduresdescribed in example 27 steps A-B starting from XLV-19 and6-quinolinecarboxylic acid. MS (ISP): 842.5 (MH⁺). ¹H-NMR (CDCl₃),diagnostic signals only: 0.86 (t, 3H), 2.35 (s, 6H), 2.49 (s, 3H),2.50-2.60 (m, 2H), 2.54 (s, 1H), 3.82 (q, 1H), 4.12-4.22 (m, 2H), 4.28(d, 1H), 4.33 (s, 1H), 5.33 (dd, 1H), 7.41-7.48 (m, 1H), 7.69 (dd, br,1H), 8.09-8.29 (m, 3H), 8.45 (s, 1H), 8.93-8.99 (m, 1H).

EXAMPLE 48

[0336] Preparation of I-48, compound of formula I, where R¹ is[2-[[[6-(1H-imidazol-1-yl)-3-pyridinyl]carbonyl]amino]ethyl]thio, R² ishydrogen, R³ is methyl and Z is oxygen.

[0337] The title compound was prepared following the proceduresdescribed in example 27 steps A-B starting from XLV-19 and6-(1H-imidazol-1-yl)-3-pyridinecarboxylic acid. MS (ISP): 858.6 (MH⁺).

EXAMPLE 49

[0338] Preparation of I-49, compound of formula I, where R¹ is[2-[(8-quinolinylcarbonyl)amino]ethyl]thio, R² is hydrogen, R³ is methyland Z is oxygen.

[0339] The title compound was prepared following the proceduresdescribed in example 27 steps A-B starting from XLV-19 and8-quinolinecarboxylic acid. MS (ISP): 842.5 (MH⁺). ¹H-NMR (CDCl₃),diagnostic signals only: 0.86 (t, 3H), 2.27 (s, 6H), 2.41-2.51 (m, 1H),2.51-2.61 (m, 1H), 2.66 (s, 1H), 2.68 (s, 3H), 3.00-3.21 (m, 4H),3.27-3.36 (m, 1H), 3.50-3.60 (m, 1H), 3.84 (q, 1H), 3.89-4.06 (m, 2H),4.23 (d, 1H), 4.32 (d, 1H), 4.37 (s, 1H), 5.49 (dd, 1H), 7.43-7.50 (m,1H), 7.62-7.70 (m, 1H), 7.93 (d, 1H), 8.25 (dd, 1H), 8.84 (dd, 1H), 9.02(dd, 1H), 11.51 (dd, br, 1H).

EXAMPLE 50

[0340] Preparation of I-50, compound of formula I, where R¹ is[2-[[[6-(1H-pyrazol-1-yl)-3-pyridinyl]carbonyl]amino]ethyl]thio, R² ishydrogen, R³ is methyl and Z is oxygen.

[0341] The title compound was prepared following the proceduresdescribed in example 27 steps A-B starting from XLV-19 and6-(1H-pyrazol-1-yl)-3-pyridinecarboxylic acid. MS (ISP): 858.6 (MH⁺).¹H-NMR (CDCl₃), diagnostic signals only: 0.88 (t, 3H), 2.29 (s, 6H),2.44-2.54 (m, 1H), 2.55 (s, 1H), 2.56 (s, 3H), 2.60-2.69 (m, 1H),2.88-2.98 (m, 1H), 3.04-3.13 (m, 2H), 3.19 (dd, 1H), 3.33-3.39 (m, 1H),3.49-3.58 (m, 1H), 3.59-3.70 (m, 1H), 3.84 (q, 1H), 4.16-4.27 (m, 2H),4.28-4.34 (m, 2H), 5.32 (dd, 1H), 6.44 (s, 1H), 7.73 (s, 1H), 7.77 (s,br, 1H), 8.02 (d, 1H), 8.38 (dd, 1H), 8.57 (d, 1H), 9.03 (d, 1H).

EXAMPLE 51

[0342] Preparation of I-51, compound of formula I, where R¹ is[2-[(1H-purin-6-yl)amino]ethyl]thio, R² is hydrogen, R3 is methyl and Zis oxygen.

[0343] The title compound was prepared following the proceduresdescribed in example 46 steps A-B starting from XLV-19 and6-chloro-1H-purine. MS (ISP): 805.6 (MH⁺). ¹H-NMR (CDCl₃), diagnosticsignals only: 0.87 (t, 3H), 2.27 (s, 6H), 2.42-2.52 (m, 1H), 2.59-2.69(m, 2H), 2.77 (s, br, 3H), 3.02-3.16 (m, 3H), 3.19 (dd, 1H), 3.31-3.41(m, 1H), 3.51-3.62 (m, 1H), 3.84 (q, 1H), 3.90-4.04 (m, br, 1H),4.15-4.26 (m, br, 1H), 4.27 (d, 1H), 4.33 (d, 1H), 4.39 (s, br, 1H),5.37 (dd, 1H), 6.67 (s, br, TH), 7.89 (s, br, 1H), 8.40 (s, br, 1H).

EXAMPLE 52

[0344] Preparation of I-52, compound of formula I, where R¹ is[2-[(6-bromo-2-methyl-quinazolin-4-yl)amino]ethyl]thio, R² is hydrogen,R³ is methyl and Z is oxygen.

[0345] The title compound was prepared following the proceduresdescribed in example 46 steps A-B starting from XLV-19 and7-bromo-4-chloro-2-methyl-quinazoline (W00220488) with the onlydifference that the reaction was run at room temperature. MS (ISP):909.5 (MH⁺). ¹H-NMR (CDCl₃), diagnostic signals only: 0.86 (t, 3H), 2.26(s, 6H), 2.41-2.50 (m, 1H), 2.58 (s, 3H), 2.59 (s, 3H), 2.61-2.68 (m,1H), 3.05-3.15 (m, 2H), 3.19 (dd, 1H)3.34-3.42 (m, 1H), 3.44-3.52 (s,br, 1H), 3.52-3.62 (m, 1H), 3.78-3.89 (m, 2H), 4.25 (d, 1H), 4.33 (d,1H), 4.34-4.44 (m, 2H), 5.33 (dd, IH), 7.11 (dd, br, 1H), 7.38-7.44 (m,1H), 7.88-7.96 (m, 2H).

EXAMPLE 53

[0346] Preparation of I-53, compound of formula I, where R¹ is[2-[[2′-methoxy-(1,1′-biphenyl)-2-yl]amino]-2-oxoethyl]thio, R² ishydrogen, R³ is methyl and Z is oxygen.

[0347] The title compound was prepared following the procedure describedin example 4 starting from XV-3 andN-[2′-methoxy-(1,1′-biphenyl)-2-yl]-2-chloro-acetamide. MS (ISP): 883.7(MH⁺).

EXAMPLE 54

[0348] Preparation of I-54, compound of formula I, where R¹ is[2-benzo[b]thien-3-yl-2-oxoethyl]thio, R² is hydrogen, R³ is methyl andZ is oxygen.

[0349] The title compound was prepared following the procedure describedin example 4 starting from XV-3 and1-benzo[b]thien-3-yl-2-bromoethanone. MS (ISP): 818.6 (MH⁺).

EXAMPLE 55

[0350] Preparation of I-55, compound of formula I, where R¹ is[2-(3,4-dimethylphenylamino)-2-oxoethyl]thio, R² is hydrogen, R³ ismethyl and Z is oxygen.

[0351] The title compound was prepared following the procedure describedin example 4 starting from XV-3 andN-(3,4-dimethylphenyl)-2-chloro-acetamide. MS (ISP): 805.69 (MH⁺).

EXAMPLE 56

[0352] Preparation of I-56 compound of formula I, where R¹ is[2-[6-amino-9H-purine-9-yl]ethyl]thio, R² is fluoro, R³ is methyl and Zis oxygen.

[0353] A] 9-(2-Iodoethyl)-6-amino-9H-purine

[0354] A suspension of 1 g (5 mmol) 9-(2-chlorooethyl)-6-amino-9H-purine(Journal of Heterocyclic Chemistry 1994, 31(2), 375-376) and 0.84 gpotassium iodide in 40 ml n-butanol was refluxed for 27 hours underargon. N-Butanol was removed in vacuo and the solid residue wassuspended in 40 ml water and the resulting slurry was stirred for 15minutes. The product was isolated by filtration, washed with 40 ml waterand dried at room temperature in vactio. Yield: 0.67 g (45.8%). MS(ISP): 290.0 (MH⁺). ¹H-NMR (DMSO-d6): 3.69 (t, 2H), 4.50 (t, 2H), 7.25(s broad, 2 H), 8.15 (s, TH), 8.17 (s, 1H).

[0355] B] (3R or S, 3aR, 4R or S, 6R, 8R, 9R, IOR, 12S, 15R,15aS)-9-[[2-O-Acetyl-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-15-ethyl-12-fluoroctahydro-8-methoxy-3-methyldithio-4,6,8,10,12,15a-hexamethyl-2H-furo[2,3-c] oxacyclotetradecin-2,5,11,13 (3H,6H,12H)-tetrone; (XV-56).

[0356] To a solution of compound XIV-1 (0.225 g, 0.273 mmol) in 5 mldichloromethane at room temperature was addeddimethyl(methylthio)sulfonium tetrafluoroborate (0.107 g, 0.546 mmol).The reaction mixture was stirred at room temperature for 30 min.Thioglycolic acid (0.075 g, 0.82 mmol) was added to the deeply browncolored mixture and the reaction mixture was stirred for 15 min. Thereaction mixture was taken up with 20 ml dichloromethane and washedtwice with 25 ml aqueous 5% Na₂CO₃, once with 25 ml water, 25 ml brineand dried over sodium sulfate. Evaporation of the solvent under reducedpressure gave 0.19 g (94%) of the title compound as a light yellow foam.MS (ISP): 750.3 (MH⁺). ¹H-NMR (CDCl₃) diagnostic signals only: 0.90 (t,3H), 1.09 (d, 3H), 1.16 (d, 3H), 1.30 (s, 3H), 1.35 (d, 3H), 1.49 (s,3H), 1,55-1,75 (m, 2H),1.78 (d, 3H), 2.06 (s, 3H), 2.26 (s, 6H), 2.59(s, 1H), 2.61 (s, 1H), 2.65 (s, 3H), 2.98- 3.15 (m),3H), 3.53 (m, 2H),4.06 (d, 1H), 4.31 (s, 1H), 4.38 (d, 1H), 4.74 (dd, 1H), 5.21(dd, 1H).

[0357] The title compound was obtained from9-(2-iodoethyl)-6-amino-9H-purine and XV-56 according to example 4. MS(ISP): 823.2 (MH⁺). ¹H-NMR (CDCl₃) diagnostic signals only: 0.89 (t,3H), 1.18 (d, 3H), 1.27.(d, 3H), 1.31 (d, 3H), 1.37 (s, 3H), 1.54 (s,3H), 1.77 (d, 3H), 1.86-2.00 (m, 2H), 2.28 (s, 6H), 2.38 (s, 1H), 2.45(m, 1H), 2.54 (s, 3H), 2.65 (m, 1H), 3.00-3.25 (m, 3H), 3.45-3.65 (m,3H), 4.09 (d, 1H), 4.23 (s, 1H), 4.32 (d, 1H), 4.46 (m, 1H), 4.67 (m,1H), 5.29 (dd, 1H), 5.53 (s broad, 2H), 8.28 (s, 1H),8.34 (s, 1H).

EXAMPLE 57

[0358] Preparation of I-57 compound of formula I, where R¹ is[3-[6-amino-9H-purine-9-yl]propyl]sulfinyl, R² is fluoro, R³ is methyland Z is oxygen.

[0359] A] Preparation of (3R or S, 3aR, 4R or S, 6R, 8R, 9R, lOR, 12S,15R, 15aS)- 3-[[2- [6-acetamido-9H-purine-9-yl]propyl]thio-9-[[2-O-acetyl-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-15-ethyl-12-fluorooctahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-2H-furo [2,3-c]oxacyclotetradecin-2,5,11,13 (3H,6H,1 2H)-tetrone (XVIII-57)

[0360] 100 mg (0.12 mmol) sulfide XII-13 were dissolved in 5 mldichloromethane and treated with 50 μl (0.48 mmol) acetic acid anhydrideand 70 μl (0.48 mmol) triethylamine. The reaction mixture was stirredfor 115 hours at room temperature. After dilution with 25 mldichloromethane, the mixture was washed twice with 25 ml 5% NaHCO₃, oncewith 25 ml water and with 25 ml brine. Evaporation gave 108 mg (98%) ofXVIII-57 as a light yellow foam. MS (ISP): 903.3 (MH⁺).

[0361] B] Preparation of (3R or S, 3aR, 4R or S, 6R, 8R, 9R, lOR, 12S,15R, 15aS)-9-[[2-O-acetyl-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-3-[[2- [6-acetamido-9H-purine-9-yl]propyll sulfinyl- 15-Ethyl-12-fluorooctahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-2H-furo [2,3-c]oxacyclotetradecin-2,5,11,13 (3H,6H,12H)-tetrone (XXXVIII-57)

[0362] 55 mg (0.06 mmol) of compound XVIII-57 acetamide dissolved in 5ml dichloromethane were treated with 51 mg (0.21 mmol)m-chloroperbenzoic acid and 35 mg sodium hydrogencarbonate at 0° C. for1 hour. 5 ml of an 10 % aqueous sodium pyrosulfate solution were addedand the two-phase system was stirred at room temperature for 1 hour. ThepH of the solution was adjusted to pH 9 with saturated sodium carbonatesolution and extracted twice with 25 ml dichloromethane. The combinedorganic extracts were washed with 25 ml 3% NaHCO₃, 25 ml brine, driedover Na2SO4 and evaporated to give 54 mg (96%) of XXXVIII-57 as a lightyellow foam. MS (ISP): 937.4 (MH⁺).

[0363] The title compound was prepared by treatment of 54 mg of crudeXXXVIII-57 with a 5% ammonia solution in methanol at room temperaturefor 48 h. Evaporation of the solvent and chromatography of the residuewith dichloromethane/methanol/ammonia 90:10:1 yielded 28 mg (55%) ofI-59 as a colorless solid. MS (ISP): 853.4 (MH⁺). ¹H-NMR (CDCl₃)diagnostic signals only: 0.91 (t, 3H), 1.16 (d, 3H), 1.21 (d, 3H), 1.27(d, 3H), 1.32 (s, 3H), 1.58 (s, 3H), 1.76 (d, 3H), 1.86-2.00 (m, 2H),2.28 (s, 6H), 2.40-2.60 (m, 3H), 2.66 (s, 3H), 2.67 (s, TH), 2.89 (m,1H), 2.95-3.25 (m, 3H), 3.48-3.70 (m, 3H), 4.05 (d, IH), 4.13 (d, TH),4.32 (d, 1H), 4.43 (t, IH), 5.46 (dd, 1H), 5.56 (s broad, 2H), 7.92 (s,IH), 8.36 (s, 1H).

EXAMPLE 58

[0364] Preparation of I-58 compound of formula I, where R¹ is[3-[6-amino-9H-purine-9-yl]propyl]sulfonyl, R² is fluoro, R³ is methyland Z is oxygen.

[0365] The title compound was prepared starting from compound XVIII-57according to example 59, steps A and B with the only difference that theoxidation step was performed with 10 equivalents of m-chloroperbenzoicacid. MS (ISP): 869.3 (MH⁺). ¹H-NMR (CDCl₃) diagnostic signals only:0.94 (t, 3H), 1.11 (d, 3H), 1.18 (d, 3H), 1.26 (d, 3H), 1.29 (d, 3H),1.62 (s, 3H), 1.77 (d, 3H), 1.86-2.00 (m, 2H), 2.29 (s, 6H), 2.40-2.70(m, 3H), 2.65 (s, 1H), 2.66(s, 3H), 3.11 (m, 1H), 3.15-3.25 (m, 3H),3.35-3.70 (m, 3H), 4.09 (d, 1H), 4.31 (d, 1H), 4.40-4.55 (m, 2H), 4.70(m, 1H), 5.50 (dd, 1H), 5.51 (s broad, 2H), 7.93 (s, 1H), 8.35(s, 1H).

EXAMPLE 59

[0366] Preparation of (3R or S, 3aS, 4R or S, 6R, 8R, 9R, IOR, 12R, 15R,15aS)-15-Ethylhexadecahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-2,5,11,13-tetraoxo-9-[[-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-N-[2-(2-pyridinyl)ethyl]-2H-furo[2,3-c] oxacyclotetradecin-3-carboxamide (1-59) compound of formula I,where R¹ is [[2-(2-pyridinyl)ethyl]amino]carbonyl, R² is hydrogen, R³ ismethyl and Z is oxygen.

[0367] A] 3-Oxo-3-[[2-(2-pyridinyl)ethyl]amino]-propanoic acidphenylmethyl ester

[0368] To an ice cold solution of 2.0 g (10.3 mmol) monobenzyl malonatein 20ml dichloromethane kept under argon were added 2.37 g (12.36 mmol)EDC*HCI and 3.7 g DMAP followed by 1.27 g (10.4 mmol)2-pyridineethaneamine. The reaction mixture was allowed to warm to roomtemperature and was stirred over night at room temperature. The solventwas evaporated and the residue was dissolved in 50 ml ethyl acetate. Theorganic layer was washed twice with 20 ml aqueous NaHCO₃ 5% and twicewith 20 ml brine, dried over Na₂SO₄ and evaporated. The crude productwas purified by flash chromatography on silica gel (CH₂Cl₂:MeOH:NH₃98:2:0.01) to give 1.9 g (62%) of the desired compound as a white solid.MS (ISP): 299.2 (MH⁺). ¹H-NMR (CDCl₃): 2.97-3.03 (m, 2H), 3.33 (s, 2H),3.60-3.75 (m, 2H), 5.15 (s, 2H), 7.11-7.17 (m, 2H), 7.29-7.39 (m, 5H),7.52 (s, br, 1H), 7.55-7.63 (m, 1H), 8.50-8.56 (m, 1H).

[0369] B] 3-Oxo-3- [[2-(2-pyridinyl)ethyl]amino]-propanoic acid

[0370] 900 mg (3.03 mmol)3-oxo-3-[[2-(2-pyridinyl)ethyl]amino]-propanoic acid phenylmethyl esterwere dissolved in 25 ml THF and 15 mg palladium on charcoal (10%) wereadded. The reaction was kept under an atmosphere of hydrogen using aballoon for 10 hours. The mixture was filtered through dicalite. Thesolids were washed with THF and methanol. The combined filtrate wasevaporated and dried under high vacuum. The crude product (300 mg) wasused without further purification for the next reaction. ¹H-NMR (CDCl₃):2.82-2.90 (m, 2H), 3.08 (s, 2H), 3.38-3.47 (m, 2H), 7.19-7.28 (m, 2H),7.65-7.74 (m, 1H), 8.16-8.24 (m, br, 1H), 8.47-8.51 (m, H).

[0371] C] (10E)-10,11-Didehydro-11-deoxy-6-O-methyl-erythromycin2′,4″-dibenzoate12-[[[[2-(2-pyridinyl)ethyl]amino]carbonyl]acetate](VIII-59)

[0372] 300 mg (1.44 mmol)3-oxo-3-[[2-(2-pyridinyl)ethyl]amino]-propanoic acid, 450 mg (0.48 mmol)of compound VI-19 and 18 mg (0.15 mmol) DMAP were suspended in 10 mldichloromethane. A solution of 300 mg (1.45 mmol) DCC in 5 mldichloromethane were added dropwise over a period of 4 hours. Thereaction was stirred for another 4 hours at room temperature and 10 mlsaturated aqueous NaHCO₃ were added. The mixture was extracted twicewith 10 ml dichloromethane. The combined organic layers were dried overNa₂SO₄ and evaporated. The crude product was purified by flashchromatography on silica gel (CH₂Cl₂:MeOH:NH₃ 98:2:0.01) to give 449 mg(83%) of the desired compound. MS (ISP): 1128.6 (MHz), 565.4 ([MH₂]⁺⁺).

[0373] D] (3R or S, 3aS, 4R or S, 6R, 8R, 9R, lOS, I IS, 12R, 15R,15aS)-9-[[2-O-Benzoyl-3,4,6-trideoxy3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-11-[[4-O-benzoyl-2,6-dideoxy-3-C-methyl-3-0-methyl-cc-L-ribo-hexopyranosyl]oxy] - 15-ethylhexadecahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-2,5,13-trioxo-N- [2-(2-pyridinyl)ethyl]-2H-furo [2,3-c]oxacyclotetradecin-3-carboxamide (IX-59)

[0374] To an ice cold solution of 250 mg (0.22 mmol) compound VIII-59 in5 ml dry THF kept under argon were added 0.28 ml (0.28 mmol) of asolution of KO^(t)Bu in THF (1M). The reaction was stirred at 0° C.during two hours. The mixture was diluted with 50 ml dichloromethane.The organic layer was washed twice with 10 ml aqueous NaHCO₃, 10 mlbrine, dried over Na₂SO₄ and evaporated. The crude product was purifiedby flash chromatography on silica gel (CH₂CI₂:MeOH:NH₃ 98:2:0.01) togive 160 mg (64%) of the desired compound. MS (ISP): 1128.6 (MH^(t)),565.3 ([MH₂]⁺⁺).

[0375] E] (3R or S, 3aS, 4R or S, 6R, 8R, 9R, lOS, llS, 12R, l5R,l5aS)-9-[[2-O-Benzoyl-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-15-ethylhexadecahydro-11-hydroxy-8-methoxy-4,6,8,10,12,15a-hexamethyl-2,5,13-trioxo-N-[2-(2-pyridinyl)ethyl]-2H-furo [2,3-c] oxacyclotetradecin-3-carboxamide(XI-59)

[0376] To a solution of 165 mg (0.146 mmol) of compound IX-59 in 5 mlethanol were added 1.54 ml HCl 2N. The reaction mixture was heated to45° C. during 24 hours. Now 1.54 ml NaOH 2N were added followed by 20 mlwater and the solution was extracted twice with 50 ml ethyl acetate. Thecombined organic layers were dried over Na₂SO₄ and evaporated. The crudeproduct was purified by flash chromatography on silica gel(CH₂Cl₂:MeOH:NH₃ 98:2:0.01) to give 66 mg (52%) of the desired compound.MS (ISP): 866.6 (MH⁺). ¹H-NMR (CDCl₃): 0.71 (d, 3H), 0.82 (t, 3H), 0.95(d, 3H), 1.00 (s, 3H), 1.08 (d, 3H), 1.13 (d, 3H), 1.29 (s, 3H), 2.25(s, 6H), 2.46-2.55 (m, 1H), 2.74-2.88 (m, 2H), 2.90-3.06 (m, 4H), 3.18(s, 3H), 3.19-3.26 (mn, 1H), 3.50-3.63 (m, 2H), 3.64-3.81 (m, 3H), 3.87(d, 1H), 4.66 (d, br, 1H), 4.78 (d, 1H), 4.92 (dd, 1H), 4.99 (dd, 1H),6.83 (dd, br, 1H), 7.10-7.20 (m, 2H), 7.40-7.47 (m, 2H), 7.51-7.64 (m,2H), 8.02-8.09 (m, 2H), 8.50-8.56 (m, 1H).

[0377] F] (3R or S, 3aS, 4R or S, 6R, 8R, 9R, IOR, I S, 12R, 15R,15aS)-9-[[2-O-Benzoyl-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-15-ethylhexadecahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-2,5,11,13-tetraoxo-N-[2-(2-pyridinyl)ethyl] - 2H-furo [2,3-c]oxacyclotetradecin-3-carboxamide (XII-59)

[0378] This compound was prepared from 30 mg (0.035 mmol) of XI-59according to the procedure described in example 1 step E. The crudeproduct was purified by flash chromatography on silica gel(CH₂Cl₂:MeOH:NH₃ 98:2:0.01) to give 23 mg (78%) of XII-59 as a mixtureof isomers. MS (ISP): 864.5 (MH⁺).

[0379] G] (3R or S, 3aS, 4R or S, 6R, 8R, 9R, IOR, 12R, 15R,15aS)-15-Ethylhexadecahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-2,5,11,13-tetraoxo-9-[[-3,4,6-trideoxy-3-(dimethylamino)-,-D-xylo-hexopyranosyl]oxy]-N-[2-(2-pyridinyl)ethyl]-2H-furo [2,3-c] oxacyclotetradecin-3-carboxamide(I-59)

[0380] The product of step F (23 mg, 0.027 mmol) was dissolved in 5 mlmethanol and stirred for 5 days at room temperature. The solvent wasremoved under reduced pressure and the product was purified by HPLCRP-C18 with a gradient of 10 to 50% acetonitrile in water/formic acid99.9:0.1. MS (ISP): 760.5 (MH⁺).

EXAMPLE 60

[0381] Preparation of I-60, compound of formula I, where R¹[[2-(3-pyridinyl)ethyl]amino]carbonyl, R² is hydrogen, R³ is methyl andZ is oxygen.

[0382] The title compound was prepared following the proceduresdescribed in example 59 steps A-G starting from monobenyzl malonate,3-pyridineethaneamine and VI-19. MS (ISP): 760.5 (MH⁺).

EXAMPLE A

[0383] Tablets of the following composition are manufactured in theusual manner: mg/tablet Active substance  500-1000 Lactose Corn starchMicrocrystalline cellulose Magnesium stearate Tablet weight 1000-1500

EXAMPLE B

[0384] Capsules of the following composition are manufactured:mg/capsule Active substance  500-1000 Lactose Corn starch Talc Capsulefill weight 1000-1500

[0385] The active substance, lactose and corn starch are firstly mixedin a mixer and then in a comminuting machine. The mixture is returned tothe mixer, the talc is added thereto and mixed thoroughly. The mixtureis filled by machine into hard gelatine capsules.

EXAMPLE C

[0386] Suppositories of the following composition are manufactured:mg/supp. Active substance 500 Suppository mass Total 1300

[0387] The suppository mass is melted in a glass or steel vessel, mixedthoroughly and cooled to 45° C. Thereupon, the finely powdered activesubstance is added thereto and stirred until it has dispersedcompletely. The mixture is poured into suppository moulds of suitablesize, left to cool, the suppositories are then removed from the mouldsand packed individually in wax paper or metal foil.

1. A compound of the formula

wherein R¹ is hydrogen, cyano or a residue -Y-X-Q; Y is S, SO, SO_(2,)NH, NCH₃, CH₂O, CH₂NH, CH₂NCH₃ or CO; X is a bond or a linear group withup to 9 atoms selected from the group consisting of C, N, O and S, ofwhich up to 2 atoms can be N, one atom can be O or S, one carbon atomcan appear as a CO group, one sulphur atom can appear as an SO₂ groupand two adjacent C atoms can be present as -CH=CH- or -C≡C-; Q ishydrogen, alkyl, heterocyclyl or aryl, which heterocyclyl and arylgroups may be further substituted; R² is hydrogen or fluorine; R³ ismethyl, -(CH₂)₃-R⁵, -CH₂CH=CH-R⁵ or -CH₂C≡C- R⁵; R⁵ is heterocyclyl oraryl, which heterocyclyl and aryl groups may be ftirther substituted; Zis or NOR⁴; R⁴ is hydrogen, alkyl, heterocyclyl, aryl, heterocyclylalkyl or aralkyl; indicates a chiral centre which is in the (R) or (S)form, i.e. including diastereomeric mixtures and separate stereomericforms, and pharmaceutically acceptable acid addition salts or in vivocleavable esters thereof, provided that not simultaneously R² ishydrogen, R³ is methyl and Z is 0 when simultaneously R¹ is hydrogen,cyano, -S(L)_(m)R⁶, -S(O)(L)_(m)R⁶, or -S(0)₂(L)_(m)R⁶; L represents-(CH₂)_(n)- or -(CH₂)_(n)Z^(l)(CH₂)_(n),-; m is 0 or 1; n is 1, 2, 3, or4; n' is 0, 1, 2, 3, or 4; Z^(l) is O, S or NH; and R⁶ is hydrogen,alkyl, heterocyclyl or aryl; which heterocyclyl and aryl groups may befurther substituted.
 2. The compound according to claim 1, wherein R³ ismethyl.
 3. The compound according to claim 1, wherein R³ is


4. The compound according to claim 1, wherein R¹ is cyano.
 5. Thecompound according to claim 1, wherein R¹ is a residue -Y-X-Q and Q is


6. The compound according to claim 1, wherein R¹ is a residue -Y-X-Q andX is a linear group with 2 to 5 atoms.
 7. The compound according toclaim 6 wherein X is (CH₂)_(n), (CH₂)_(m)OCH₂, (CH₂)₂NCH₃(CH₂)₂ or(CH₂)_(p)COW; where n and p are 1-3, m is 0-3 and W is absent or O orNH.
 8. The compound according to claim 1, wherein R¹ is a residue -Y-X-Qand Y is S, SO₂ or CO.
 9. The compound according to claim 8, wherein Yis S.
 10. The compound according to claim 1, wherein R¹ is a residue-Y-X-Q and Y is CH₂O, NH or CH₂NH.
 11. The compound according to claim1, wherein R¹ is


12. The compound according to formula I in claim 1, wherein R¹ is[(4-methoxyphenyl) methyl]thio, R² is fluoro, R³ is methyl and Z isoxygen; R¹ is [(4-methoxyphenyl)methyl]sulfonyl, R² is fluoro, R³ ismethyl and Z is oxygen; R¹ is [2-(2-amino-quinolin-8-yl)2-oxo-ethyl]thio, R² is hydrogen, R³ is methyl and Z is oxygen; R¹ is[2-methoxy-2-oxoethyl]-thio, R² is hydrogen, R³ is methyl and Z isoxygen R¹ is [2-(3,4-dihydro-1H-2-oxo-quinolin-6-yl)-2-oxoethyl]thio, R²is hydrogen, R³ is methyl and Z is oxygen; R¹ is[2-oxo-2-(pyridin-2-yl)ethyl]-thio, R² is hydrogen, R³ is methyl and Zis oxygen; R¹ is 3-[3-oxo-3-(1,2,3,4-tetrahydro-isoquinolin-2-yl)propyl]thio, R² is hydrogen, R³ is methyl and Z isoxygen; R¹ is 3-[[[2-(6-amino-9H-purin-9-yl)ethyl]methylamino]-ethyl]thio, R²is hydrogen, R³ is methyl and Z is oxygen; R¹is [3-(4-phenyl-1H-pyrazol-1-yl)-propyl]thio, R² is fluoro, R³ is methyland Z is oxygen; R¹ is [3-(4-phenyl-1H-pyrazol-1-yl)-propyl]sulfonyl, R²is fluoro R³ is methyl and Z is oxygen; R¹ is [2-[[5-methyl-2,4-(1H,3H)-pyrimidinedione- 1-yl]methoxy]ethyl]thio, R² isfluoro, R³is methyl and Z is oxygen; R¹ is cyano, R² is hydrogen, R³ is3-(3-quinolyl)-2-propen-1-yl and Z is oxygen; or R¹ is(phenylmethoxy)carbonyl, R² is hydrogen, R³ is methyl and Z is oxygen;and pharmaceutically acceptable acid addition salts thereof.
 13. Thecompound according to formula I in claim 1, wherein R¹ is selected fromthe group consisting of [2-[4-(dimethylamino)phenyl]-2-oxoethyl]thio,[2-(1H-2,3-dihydroindol-1-yl)-2-oxoethyl]thio,[2-[(3-pyridinylcarbonyl)ramino]ethyl]thio, [2-[(2,1,3-benzoxadiazol-5-ylcarbonyl)amino]ethyl]thio,[2-[[[5-(2-pyridinyl)thien-2-yl]sulfonyl]amino]ethyl]thio, [2-[[(2,1,3-benzoxadiazol-4-yl)sulfonyl]amino]ethyl]thio,[3-(4-cyanophenyl)prop-2-ynyl]thio,[2-[[(phenylmethyl)amino]sulfonyl]ethyl]thio, [2-(8-quinolinylamino)-2-oxoethyl]thio, [2-(5-quinolinylamino) -2-oxoethyl]thio,[2-[(3-quinolinylcarbonyl)amino]ethyl]thio, [2-[[[5-(dimethylamino)-1-naphthalenyl]sulfonyl]amino]ethyl]thio,[2-[[(8-quinolinyl)sulfonyl]amino]ethyl]thio,[2-[[(1,3-benzodioxol-5-yl)methyl]amino]-2-oxoethyl]thio,[2-[(2-furanylmethyl)amino]-2-oxoethyl]thio,[2-[(2-pyridinylmethyl)amino]-2-oxoethyl]thio,[2-[(5-methyl-3-isoxazolyl)amino]-2-oxoethyl]thio,[2-[(2-benzothiazolylmethyl)amino]-2-oxoethyl]thio,[2-[(1H-imidazol-2-ylmethyl)amino]-2-oxoethyl]thio,[3-(5-quinolinylamino)-3-oxopropyl]thio,[2-(2-quinolinylamino)-2-oxoethyl]thio,[2-(6-quinolinylamino)-2-oxoethyl]thio,[2-(3-quinolinylamino)-2-oxoethyl]thio,[2-(5-isoquinolinylamino)-2-oxoethyl]thio,[3-(6-quinolinylamino)-3-oxopropyl]thio,[3-(3-quinolinylamino)-3-oxopropyl]thio,[2-[(3-pyridinylcarbonyl)amino]ethyl]sulfonyl,[2-[(2,1,3-benzoxadiazol-5-ylcarbonyl)amino]ethyl]sulfonyl,[2-[2,4-dimethoxyphenyl]-2-oxoethyl]thio,[2-[(5-cyanopyridin-2-yl)amino]ethyl]thio,[2-[(6-quinolinylcarbonyl)amino]ethyl]thio,[2-[[[6-(1H-imidazol-1-yl)-3-pyridinyl]carbonyl]amino]ethyl]thio,[2-[(8-quinolinylcarbonyl)amino]ethyl]thio,[2-[[[6-(1H-pyrazol-1-yl)-3-pyridinyl]carbonyl]amino]ethyl]thio,[2-[(1H-purin-6-yl)amino]ethyl]thio,[2-[(6-bromo-2-methyl-quinazolin-4-yl)amino]ethyl]thio,[2-[[2′-methoxy(1,1′-biphenyl)-2-yl]amino]-2-oxoethyl]thio,[2-benzo[b]thien-3-yl-2-oxoethyl]thio,[2-(3,4-dimethylphenylamino)-2-oxoethyl]thio,[2-[6-amino-9H-purine-9-yl]ethyl]thio,[3-[6-amino-9H-purine-9-yl]propyl]sulfinyl,[3-[6-amino-9H-purine-9-yl]propyl]sulfonyl,[[2-(2-pyridinyl)ethyl]amino]carbonyl, and[[2-(3-pyridinyl)ethyl]amino]carbonyl; and pharmaceutically acceptableacid addition salts thereof.
 14. The compound according to formula I inclaim 1, wherein R¹ is[2-[3-(3-pyridinyl)-1H-1,2,4-triazol-i-yl]ethyl]thio, R² is fluoro, R³is methyl and Z is oxygen, said compound being named (3R or S, 3aR, 4Ror S, 6R, 8R, 9R, 10R, 12S, 15R,15aS)-15-Ethyl-12-fluorooctahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-3-[[2-[3-(3-pyridinyl)-1H-1,2,4-triazol- 1-yl]ethyl]thio]-9-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-2H-furo[2,3-c] oxacyclotetradecin-2,5, 11,13 (3H,6H, 12H)-tetrone andpharmaceutically acceptable acid addition salts thereof.
 15. Thecompound according to formula I in claim 1, wherein R¹ is[3-[6-Amino-9H-purine-9-yl]propyl]thio, R² is fluoro, R³ is methyl and Zis oxygen, said compound being named (3R or S, 3aR, 4R or S, 6R, 8R, 9R,IOR, 12S, 15R,15aS)-3-[[3-[6-Amino-9H-purine-9-yl]propyl]thio]-15-ethyl-12-fluorooctahydro-8-methoxy-4,6,8,10,12,15a-hexamethyl-3-9-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-2H-furo[2,3-c] oxacyclotetradecin-2,5,11,13 (3H,6H, 12H) -tetrone andpharmaceutically acceptable acid addition salts thereof.
 16. A compoundof the formula

wherein R¹ is hydrogen, cyano or a residue -Y-X-Q; Y is S, SO, SO₂, NH,NCH₃, CH₂O, CH₂NH, CH₂NCH₃ or CO; X is a bond or a linear group with upto 9 atoms selected from the group consisting of C, N, O and S, of whichup to 2 atoms can be N, one atom can be O or S, one carbon atom canappear as a CO group, one sulphur atom can appear as an SO₂ group andtwo adjacent C atoms can be present as -CH=CH- or -C≡C-; Q is hydrogen,alkyl, heterocyclyl or aryl, which heterocyclyl and aryl groups may befurther substituted; R² is hydrogen or fluorine; R³ is methyl,-(CH₂)₃-R⁵, -CH₂CH=CH-R⁵ or -CH₂C≡C- R⁵; R⁵ is heterocyclyl or aryl,which heterocyclyl and aryl groups may be fuirther substituted; Z is Oor NOR⁴; R⁴ is hydrogen, alkyl, heterocyclyl, aryl, heterocyclyl alkylor aralkyl; indicates a chiral centre which is in the (R) or (S) form,i.e. including diastereomeric mixtures and separate stereomeric forms;and Rp_(l) is acetyl or benzoyl, and pharmaceutically acceptable acidaddition salts or in vivo cleavable esters thereof.
 17. A process formaking the compound of claim I, comprising deacylating a compound of theformula

wherein R¹ is hydrogen, cyano or a residue -Y-X-Q; Y is S, SO, SO_(2,)NH, NCH₃, CH₂O, CH₂NH, CH₂NCH₃ or CO; X is a bond or a linear group withup to 9 atoms selected from the group consisting of C, N, O and S, ofwhich up to 2 atoms can be N, one atom can be O or S, one carbon atomcan appear as a CO group, one sulphur atom can appear as an SO₂ groupand two adjacent C atoms can be present as -CH=CH- or -C≡C-; Q ishydrogen, alkyl, heterocyclyl or aryl, which heterocyclyl and arylgroups may be further substituted; R² is hydrogen or fluorine; R³ ismethyl, -(CH₂)₃-R⁵, -CH₂CH=CH-R⁵ or -CH₂C≡C- R⁵; R⁵ is heterocyclyl oraryl, which heterocyclyl and aryl groups may be further substituted; Zis O or NOR⁴; R⁴ is hydrogen, alkyl, heterocyclyl, aryl, heterocyclylalkyl or aralkyl; indicates a chiral centre which is in the (R) or (S)form, i.e. including diastereomeric mixtures and separate stereomericforms; and Rp_(l) is acetyl or benzoyl, and pharmaceutically acceptableacid addition salts or in vivo cleavable esters thereof.
 18. A method oftreating or preventing infectious diseases comprising administering to apatient in need thereof, an effective amount of a compound according toclaim
 1. 19. A pharmaceutical composition comprising a compoundaccording to claim 1 and a pharmaceutically acceptable carrier orexcipient.
 20. A compound of the formula

wherein R¹ is hydrogen or a residue -Y-X-Q; Y is S. SO, SO_(2,) or CO; Xis a bond or a linear group with up to 9 atoms selected from the groupconsisting of C, N, O and S, of which up to 2 atoms can be N, one atomcan be O or S, one carbon atom can appear as a CO group, one sulphuratom can appear as an SO₂ group and two adjacent C atoms can be presentas -CH=CH- or -C≡C-; Q is selected from the group consisting of

R² is hydrogen or fluorine; R³ is methyl; R⁵ is heterocyclyl or aryl,which heterocyclyl and aryl groups may be further substituted; Z is O;R⁴ is hydrogen, alkyl, heterocyclyl, aryl, heterocyclyl alkyl oraralkyl; indicates a chiral centre which is in the (R) or (S) form, i.e.including diastereomeric mixtures and separate stereomeric forms, andpharmaceutically acceptable acid addition salts or in vivo cleavableesters thereof